245 results on '"Cassatella MA"'
Search Results
2. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
- Author
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Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, Zychlinsky, A, Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, and Zychlinsky, A
- Abstract
These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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- 2019
3. Neutrophils in innate and adaptive immunity
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Jaillon S, Galdiero MR, Del Prete D, Cassatella MA, Garlanda C, and Mantovani A.
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- 2013
4. IL-10 fails to downregulate cytokine expression and production by LPS-treated neutrophils and monocytes of Hyper-IgE Syndrome patients
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Giacomelli, M., Tamassia, N., Vairo, D., Soresina, A., Giliani, Silvia Clara, Moratto, D., Bertulli, C., Plebani, Alessandro, Cassatella, Ma, Bazzoni, F., and Badolato, Raffaele
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- 2010
5. Differential regulation of chemokine production by Fcgamma receptor engagement in human monocytes: association of CCL1 with a distinct form of M2 monocyte activation
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Sironi, M, Martinez, Fo, D'Ambrosio, D, Gattorno, M, Polentarutti, N, Locati, M, Gregorio, A, Iellem, A, Cassatella, Ma, VAN DAMME, J, Sozzani, Silvano, Martini, A, Sinigaglia, F, Vecchi, A, and Mantovani, A.
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- 2006
6. Sjogren's syndrome salivary gland ductal epithelial cells display defective scavenging of CXCL10
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Punzi, L., Todesco, S., Agostini, C., Cassatella, Ma, Calabrese, F., Baesso, I., Contri, A., Facco, M., Miorin, M., Oliviero, F., and PAOLO SFRISO
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- 2005
7. CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A(1)
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Scapini, P, Morini, M, Tecchio, C, Minghelli, S, DI CARLO, E, Tanghetti, E, Albini, A, Lowell, C, Berton, G, Noonan, Douglas, and Cassatella, Ma
- Published
- 2004
8. Evidence for the involvement of distinct signal transduction pathways in the regulation of constitutive and interferon gamma-dependent gene expression of NADPH oxidase components (gp91-phox, p47-phox, and p22- phox) and high-affinity receptor for IgG (Fc gamma R-I) in human polymorphonuclear leukocytes
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Amezaga, MA, primary, Bazzoni, F, additional, Sorio, C, additional, Rossi, F, additional, and Cassatella, MA, additional
- Published
- 1992
- Full Text
- View/download PDF
9. Generation of superoxide anion by alveolar macrophages in sarcoidosis: evidence for the activation of the oxigen metabolism in patients with high intensity alveolitis
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Cassatella, Ma, Berton, G, Agostini, Carlo, Zambello, R, Trentin, Livio, Cipriani, A, and Semenzato, GIANPIETRO CARLO
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- 1989
10. Presence of cytochrome b-245 in NADPH oxidase preparations from humanneutrophils
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Bellavite, P, Cassatella, Ma, Papini, Emanuele, Megyeri, P, and Rossi, F.
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- 1986
11. Epigenetic regulation of neutrophil development and function
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Gioacchino Natoli, Marco A. Cassatella, Renato Ostuni, Nicola Tamassia, Ostuni, R, Natoli, G, Cassatella, Ma, and Tamassia, N.
- Subjects
0301 basic medicine ,Neutrophils ,Granulopoiesis ,Cellular differentiation ,Immunology ,Biology ,Epigenesis, Genetic ,Proinflammatory cytokine ,03 medical and health sciences ,Animals ,Humans ,Immunology and Allergy ,Epigenetics ,Transcription factor ,Cytokine ,Epigenomics ,Myelopoiesis ,Regulation of gene expression ,Neutrophil ,Epigenetic ,Cell Differentiation ,DNA Methylation ,Immunity, Innate ,Chromatin ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,Cytokines - Abstract
In addition to performing well-defined effector functions, neutrophils are now recognized as versatile and sophisticated cells with critical immunoregulatory roles. These include the release of a variety of proinflammatory or immunosuppressive cytokines, as well as the expression of genes with regulatory functions. Neutrophils share broad transcriptional features with monocytes, in keeping with the close developmental relation between the two cell types. However, neutrophil-specific gene expression patterns conferring cell type-specific responses to bacterial, viral or fungal components have been identified. Accumulating evidence suggest that these differences reflect the peculiar epigenomic and regulatory landscapes of neutrophils and monocytes, in turn controlled by the specific lineage-determining transcription factors shaping their identity. In this review, we will describe current knowledge on how neutrophil identity and function are controlled at the molecular level, focusing on transcriptional and chromatin regulation of neutrophil development and activation in response to inflammatory stimuli.
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- 2016
12. Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils
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Maili Zimmermann, Monica Castellucci, Francisco Bianchetto Aguilera, Marco A. Cassatella, Nicola Tamassia, Marzia Rossato, Gioacchino Natoli, Renato Ostuni, Flavia Bazzoni, Sara Costa, Giampiero Girolomoni, Claudio Lunardi, Zimmermann, M, Aguilera, Fb, Castellucci, M, Rossato, M, Costa, S, Lunardi, C, Ostuni, R, Girolomoni, G, Natoli, G, Bazzoni, F, Tamassia, N, and Cassatella, Ma.
- Subjects
Neutrophils ,General Physics and Astronomy ,Chromatin remodelling ,Ligands ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Neutrophil Activation ,Histones ,Transcription (biology) ,Granulocyte Colony-Stimulating Factor ,Interleukin-12 Receptor beta 1 Subunit ,Animals ,Humans ,RNA, Messenger ,Interleukin 6 ,Autocrine signalling ,Enhancer ,Promoter Regions, Genetic ,Adaptor Proteins, Signal Transducing ,Inflammation ,IL-6 ,Multidisciplinary ,biology ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Toll-Like Receptors ,Imidazoles ,Signal transducing adaptor protein ,Nuclear Proteins ,General Chemistry ,TLR8 ,Chromatin remodelling, TNF-alpha, IL-6, neutrophils ,Chromatin Assembly and Disassembly ,Mice, Inbred C57BL ,Autocrine Communication ,Interleukin 1 Receptor Antagonist Protein ,Enhancer Elements, Genetic ,Genetic Loci ,TLR4 ,biology.protein ,Cancer research ,Tumor necrosis factor alpha ,I-kappa B Proteins ,Peritoneum ,Protein Processing, Post-Translational ,TNF-alpha ,Protein Binding ,Transcription Factors - Abstract
Controversy currently exists about the ability of human neutrophils to produce IL-6. Here, we show that the chromatin organization of the IL-6 genomic locus in human neutrophils is constitutively kept in an inactive configuration. However, we also show that upon exposure to stimuli that trigger chromatin remodelling at the IL-6 locus, such as ligands for TLR8 or, less efficiently, TLR4, highly purified neutrophils express and secrete IL-6. In TLR8-activated neutrophils, but not monocytes, IL-6 expression is preceded by the induction of a latent enhancer located 14 kb upstream of the IL-6 transcriptional start site. In addition, IL-6 induction is potentiated by endogenous TNFα, which prolongs the synthesis of the IκBζ co-activator and sustains C/EBPβ recruitment and histone acetylation at IL-6 regulatory regions. Altogether, these data clarify controversial literature on the ability of human neutrophils to generate IL-6 and uncover chromatin-dependent layers of regulation of IL-6 in these cells.
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- 2015
13. Cutting edge : an inactive chromatin configuration at the IL-10 locus in human neutrophils
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Sven Brandau, Kirsten Bruderek, Bastian Schilling, Gioacchino Natoli, Flavia Bazzoni, Nicola Tamassia, Renato Ostuni, Maili Zimmermann, Marco A. Cassatella, Monica Castellucci, Tamassia, N, Zimmermann, M, Castellucci, M, Ostuni, R, Bruderek, K, Schilling, B, Brandau, S, Bazzoni, F, Natoli, G, and Cassatella, Ma.
- Subjects
Chromatin Immunoprecipitation ,Skin Neoplasms ,Neutrophils ,Protein Conformation ,Immunology ,Medizin ,Locus (genetics) ,Methylation ,Synteny ,Monocytes ,Histones ,chromatin modification ,Mice ,Species Specificity ,medicine ,Animals ,Humans ,Immunology and Allergy ,Melanoma ,Gene ,Cells, Cultured ,biology ,medicine.disease ,Molecular biology ,Chromatin ,Interleukin-10 ,Interleukin 10 ,Enhancer Elements, Genetic ,Histone ,Gene Expression Regulation ,Genetic Loci ,IL-10 ,biology.protein ,H3K4me3 ,Protein Processing, Post-Translational - Abstract
To identify the molecular basis of IL-10 expression in human phagocytes, we evaluated the chromatin modification status at their IL-10 genomic locus. We analyzed posttranslational modifications of histones associated with genes that are active, repressed, or poised for transcriptional activation, including H3K4me3, H4Ac, H3K27Ac, and H3K4me1 marks. Differently from autologous IL-10–producing monocytes, none of the marks under evaluation was detected at the IL-10 locus of resting or activated neutrophils from healthy subjects or melanoma patients. By contrast, increased H3K4me3, H4Ac, H3K4me1, and H3K27Ac levels were detected at syntenic regions of the IL-10 locus in mouse neutrophils. Altogether, data demonstrate that human neutrophils, differently from either monocytes or mouse neutrophils, cannot switch on the IL-10 gene because its locus is in an inactive state, likely reflecting a neutrophil-specific developmental outcome. Implicitly, data also definitively settle a currently unsolved issue on the capacity of human neutrophils to produce IL-10.
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- 2013
14. IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukaemic cells
- Author
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Tecchio C, Huber V, Scapini P, Calzetti F, Margotto D, Todeschini G, Pilla L, Pizzolo G, Rivoltini L, Cassatella M.A., MARTINELLI, GIOVANNI, Tecchio C, Huber V, Scapini P, Calzetti F, Margotto D, Todeschini G, Pilla L, Martinelli G, Pizzolo G, Rivoltini L, and Cassatella MA.
- Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily exerting cytotoxic activities toward tumor cells. Herein, we demonstrate that therapeutic concentrations of interferon alpha (IFNalpha) stimulate the expression of high levels of TRAIL mRNA and the release of elevated amounts of a soluble bioactive form of TRAIL (sTRAIL) in both human neutrophils and monocytes. Supernatants harvested from IFNalpha-treated neutrophils/monocytes elicited, on TRAIL-sensitive leukemic cell lines, proapoptotic activities that were significantly reduced by either a combination of TRAIL-R1/Fc and TRAIL-R2/Fc chimeras or neutralizing anti-TRAIL, anti-TRAIL-R1, and anti-TRAIL-R2 antibodies, suggesting that they were mediated by released sTRAIL acting on both TRAIL receptors. Since diseases such as chronic myeloid leukemia (CML) and melanoma are effectively treated with IFNalpha,we also demonstrate that CML neutrophils and peripheral blood mononuclear cells (PBMCs) cultured with IFNalpha at therapeutic concentrations retain the capacity of releasing sTRAIL, suggesting that CML leukocytes, in vivo, might represent an important source of sTRAIL. In this regard, we show that sTRAIL serum levels as well as leukocyte-associated TRAIL significantly increase in melanoma patients following IFNalpha administration. Collectively, these findings indicate that sTRAIL released by IFNalpha-activated neutrophils and monocytes contributes not only to the immunoregulatory actions but also to the therapeutic activities of IFNalpha.
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- 2004
15. How murine neutrophils are hijacked within the microenvironment of pancreatic cancer.
- Author
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Cassatella MA, Scapini P, and Tamassia N
- Subjects
- Humans, Animals, Mice, Tumor Microenvironment physiology, Neutrophils pathology, Pancreatic Neoplasms
- Abstract
Discoveries made in the past decades have brought out that, in addition to their classical primary defensive functions against infections, polymorphonuclear neutrophils play key effector roles not only in chronic inflammatory and immune-mediated diseases but also in cancer. In addition, depending on their differentiation/activation status and/or on the physiological or pathological microenvironment in which they reside, neutrophils have been shown to behave as highly plastic cells, able to acquire new phenotypes/functional states. All these features are well manifested in cancer and modulated during tumor progression. Herein, we discuss intriguing data by Lai Ng's group that have shed light on the origin and development of terminally differentiated, proangiogenic, tumor-associated neutrophils, facilitating tumor growth in a murine orthotopic model of pancreatic ductal adenocarcinoma. These findings help to progress toward the ambitious goal of selectively targeting only the skewed pathological neutrophil populations present within the tumor microenvironment., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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16. Human CD34+/dim neutrophil-committed progenitors do not differentiate into neutrophil-like CXCR1+CD14+CD16- monocytes in vitro.
- Author
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Signoretto I, Calzetti F, Gasperini S, Bianchetto-Aguilera F, Gardiman E, Finotti G, Tecchio C, Tamassia N, and Cassatella MA
- Subjects
- Humans, Antigens, CD34 metabolism, Flow Cytometry, Neutrophils metabolism, Monocytes metabolism
- Abstract
The advent of recent cutting-edge technologies has allowed the discovery and characterization of novel progenitors of human neutrophils, including SSCloCD66b+CD15+CD11b-CD49dhiproNeu1s, SSChiCD66b+CD15+CD11b-CD49dintproNeus2s, CD66b+CD15+CD11b+CD49d+CD101-preNeus, and Lin-CD66b+CD117+CD71+eNePs. In this research field, we recently identified CD66b-CD38+CD64dimCD115-, CD34+, and CD34dim/- cells exclusively committed to the neutrophil lineage (which we renamed as CD34+ and CD34dim/- neutrophil-committed progenitors), representing the earliest neutrophil precursors identifiable and sorted by flow cytometry. Moreover, based on their differential CD34 and CD45RA expression, we could identify 4 populations of neutrophil-committed progenitors: CD34+CD45RA-/NCP1s, CD34+CD45RA+/NCP2s, CD34dim/-CD45RA+/NCP3s, and CD34dim/-CD45RA-/NCP4s. This said, a very recent study by Ikeda and coworkers (PMID: 36862552) reported that neutrophil precursors, termed either neutrophil progenitors or "early neutrophil-committed progenitors," would generate immunosuppressive neutrophil-like CXCR1+CD14+CD16- monocytes. Hence, presuming that neutrophil progenitors/"early neutrophil-committed progenitors" correspond to neutrophil-committed progenitors, the selective neutrophil commitment that we attributed to neutrophil-committed progenitors is contradicted by Ikeda and coworkers' article. In this study, by performing a more analytical reevaluation at the phenotypic and molecular levels of the cells generated by neutrophil-committed progenitors 2 and 4 (selected as representatives of neutrophil-committed progenitors), we categorically exclude that neutrophil-committed progenitors generate neutrophil-like CXCR1+CD14+CD16- monocytes. Rather, we provide substantial evidence indicating that the cells generated by neutrophil progenitors/"early neutrophil-committed progenitors" are neutrophilic cells at a different stage of maturation, displaying moderate levels of CD14, instead of neutrophil-like CXCR1+CD14+CD16- monocytes, as pointed by Ikeda and coworkers. Hence, the conclusion that neutrophil progenitors/"early neutrophil-committed progenitors" aberrantly differentiate into neutrophil-like monocytes derives, in our opinion, from data misinterpretation., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2024
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17. Surface CD52, CD84, and PTGER2 mark mature PMN-MDSCs from cancer patients and G-CSF-treated donors.
- Author
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Pettinella F, Mariotti B, Lattanzi C, Bruderek K, Donini M, Costa S, Marini O, Iannoto G, Gasperini S, Caveggion E, Castellucci M, Calzetti F, Bianchetto-Aguilera F, Gardiman E, Giani M, Dusi S, Cantini M, Vassanelli A, Pavone D, Milella M, Pilotto S, Biondani P, Höing B, Schleupner MC, Hussain T, Hadaschik B, Kaspar C, Visco C, Tecchio C, Koenderman L, Bazzoni F, Tamassia N, Brandau S, Cassatella MA, and Scapini P
- Subjects
- Humans, Neutrophils, Receptors, Prostaglandin E, EP2 Subtype metabolism, Granulocyte Colony-Stimulating Factor pharmacology, Granulocyte Colony-Stimulating Factor metabolism, CD52 Antigen metabolism, Signaling Lymphocytic Activation Molecule Family metabolism, Myeloid-Derived Suppressor Cells metabolism, Myeloid-Derived Suppressor Cells pathology, Neoplasms pathology
- Abstract
Precise molecular characterization of circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is hampered by their mixed composition of mature and immature cells and lack of specific markers. Here, we focus on mature CD66b
+ CD10+ CD16+ CD11b+ PMN-MDSCs (mPMN-MDSCs) from either cancer patients or healthy donors receiving G-CSF for stem cell mobilization (GDs). By RNA sequencing (RNA-seq) experiments, we report the identification of a distinct gene signature shared by the different mPMN-MDSC populations under investigation, also validated in mPMN-MDSCs from GDs and tumor-associated neutrophils (TANs) by single-cell RNA-seq (scRNA-seq) experiments. Analysis of such a gene signature uncovers a specific transcriptional program associated with mPMN-MDSC differentiation and allows us to identify that, in patients with either solid or hematologic tumors and in GDs, CD52, CD84, and prostaglandin E receptor 2 (PTGER2) represent potential mPMN-MDSC-associated markers. Altogether, our findings indicate that mature PMN-MDSCs distinctively undergo specific reprogramming during differentiation and lay the groundwork for selective immunomonitoring, and eventually targeting, of mature PMN-MDSCs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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18. Plasmacytoid Dendritic Cell, Slan + -Monocyte and Natural Killer Cell Counts Function as Blood Cell-Based Biomarkers for Predicting Responses to Immune Checkpoint Inhibitor Monotherapy in Non-Small Cell Lung Cancer Patients.
- Author
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Pettinella F, Lattanzi C, Donini M, Caveggion E, Marini O, Iannoto G, Costa S, Zenaro E, Fortunato TM, Gasperini S, Giani M, Belluomini L, Sposito M, Insolda J, Scaglione IM, Milella M, Adamo A, Poffe O, Bronte V, Dusi S, Cassatella MA, Ugel S, Pilotto S, and Scapini P
- Abstract
The advent of immune checkpoint inhibitors (ICIs), for instance, programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockers, has greatly improved the outcome of patients affected by non-small cell lung cancer (NSCLC). However, most NSCLC patients either do not respond to ICI monotherapy or develop resistance to it after an initial response. Therefore, the identification of biomarkers for predicting the response of patients to ICI monotherapy represents an urgent issue. Great efforts are currently dedicated toward identifying blood-based biomarkers to predict responses to ICI monotherapy. In this study, more commonly utilized blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR) and the lung immune prognostic index (LIPI) score, as well as the frequency/number and activation status of various types of circulating innate immune cell populations, were evaluated in NSCLC patients at baseline before therapy initiation. The data indicated that, among all the parameters tested, low plasmacytoid dendritic cell (pDC), slan
+ -monocyte and natural killer cell counts, as well as a high LIPI score and elevated PD-L1 expression levels on type 1 conventional DCs (cDC1s), were independently correlated with a negative response to ICI therapy in NSCLC patients. The results from this study suggest that the evaluation of innate immune cell numbers and phenotypes may provide novel and promising predictive biomarkers for ICI monotherapy in NSCLC patients.- Published
- 2023
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19. slan+ Monocytes Kill Cancer Cells Coated in Therapeutic Antibody by Trogoptosis.
- Author
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Finotti G, Pietronigro E, Balanzin C, Lonardi S, Constantin G, Chao MP, Tecchio C, Vermi W, and Cassatella MA
- Subjects
- Humans, Rituximab pharmacology, Rituximab therapeutic use, Antibodies, Monoclonal, Humanized metabolism, Coculture Techniques, Antibody-Dependent Cell Cytotoxicity, Monocytes, Neoplasms drug therapy
- Abstract
Monocytes positive for 6-Sulfo LacNAc (slan) are a major subset of nonclassical CD14dimCD16+ monocytes in humans. We have shown that slan+ cells infiltrate lymphomas and elicit an antibody-dependent cellular cytotoxicity (ADCC) of neoplastic B cells mediated by the anti-CD20 therapeutic rituximab. Herein, by performing blocking experiments and flow cytometry analyses, as well as confocal microscopy and live-cell imaging assays, we extended the findings to other humanized antibodies and deciphered the underlying effector mechanism(s). Specifically, we show that, after coculture with target cells coated with anti-CD20 or anti-CD38, slan+ monocytes mediate trogocytosis, a cell-cell contact dependent, antibody-mediated process that triggers an active, mechanic disruption of target cell membranes. Trogocytosis by slan+ monocytes leads to a necrotic type of target cell death known as trogoptosis, which, once initiated, was partially sustained by endogenous TNFα. We also found that slan+ monocytes, unlike natural killer (NK) cells, mediate a direct ADCC with all types of anti-CD47 analyzed, and this was independent of their IgG isotype. The latter findings unveil a potentially relevant contribution by slan+ monocytes in mediating the therapeutic efficacy of anti-CD47 in clinical practice, which could be particularly important when NK cells are exhausted or deficient in number. Overall, our observations shed new light on the cytotoxic mechanisms exerted by slan+ monocytes in antibody-dependent tumor cell targeting and advance our knowledge on how to expand our therapeutic arsenal for cancer therapy., (©2023 American Association for Cancer Research.)
- Published
- 2023
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20. The slan antigen identifies the prototypical non-classical CD16 + -monocytes in human blood.
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Tamassia N, Bianchetto-Aguilera F, Gasperini S, Grimaldi A, Montaldo C, Calzetti F, Gardiman E, Signoretto I, Castellucci M, Barnaba V, Tripodi M, and Cassatella MA
- Subjects
- Humans, Leukocytes, Mononuclear, Monocytes, Proteomics
- Abstract
Introduction: Peripheral monocytes in humans are conventionally divided into classical (CL, CD14
++ CD16- ), intermediate (INT, CD14++ CD16+ ) and non-classical (NC, CD14dim/- CD16++ ) cells, based on their expression levels of CD14 and CD16. A major fraction of the NC-monocytes has been shown to express the 6-sulfo LacNAc (slan) antigen, but whether these slan+ /NC-monocytes represent the prototypical non-classical monocytes or whether they are simply a sub-fraction with identical features as the remainder of NC monocytes is still unclear., Methods: We analyzed transcriptome (by bulk and single cell RNA-seq), proteome, cell surface markers and production of discrete cytokines by peripheral slan+ /NC- and slan- /NC-monocytes, in comparison to total NC-, CL- and INT- monocytes., Results: By bulk RNA-seq and proteomic analysis, we found that slan+ /NC-monocytes express higher levels of genes and proteins specific of NC-monocytes than slan- /NC-monocytes do. Unsupervised clustering of scRNA-seq data generated one cluster of NC- and one of INT-monocytes, where all slan+ /NC-monocytes were allocated to the NC-monocyte cluster, while slan- /NC-monocytes were found, in part (13.4%), within the INT-monocyte cluster. In addition, total NC- and slan- /NC-monocytes, but not slan+ /NC-monocytes, were found by both bulk RNA-seq and scRNA-seq to contain a small percentage of natural killer cells., Conclusion: In addition to comparatively characterize total NC-, slan- /NC- and slan+ /NC-monocyte transcriptomes and proteomes, our data prove that slan+ /NC-, but not slan- /NC-, monocytes are more representative of prototypical NC-monocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LZ-H declared a shared committee with one of the authors MAC to the handling editor., (Copyright © 2023 Tamassia, Bianchetto-Aguilera, Gasperini, Grimaldi, Montaldo, Calzetti, Gardiman, Signoretto, Castellucci, Barnaba, Tripodi and Cassatella.)- Published
- 2023
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21. Immune checkpoint blockade therapy mitigates systemic inflammation and affects cellular FLIP-expressing monocytic myeloid-derived suppressor cells in non-progressor non-small cell lung cancer patients.
- Author
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Adamo A, Frusteri C, Pilotto S, Caligola S, Belluomini L, Poffe O, Giacobazzi L, Dusi S, Musiu C, Hu Y, Wang T, Rizzini D, Vella A, Canè S, Sartori G, Insolda J, Sposito M, Incani UC, Carbone C, Piro G, Pettinella F, Qi F, Wang D, Sartoris S, De Sanctis F, Scapini P, Dusi S, Cassatella MA, Bria E, Milella M, Bronte V, and Ugel S
- Subjects
- Humans, Monocytes, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Myeloid-Derived Suppressor Cells, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1β in only NP patients after ICI treatment. Moreover, using t -distributed stochastic neighbor embedding ( t -SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2023
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22. Current knowledge on the early stages of human neutropoiesis.
- Author
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Calzetti F, Finotti G, and Cassatella MA
- Subjects
- Humans, Hematopoietic Stem Cells, Bone Marrow Cells, Neutrophils, Bone Marrow
- Abstract
Polymorphonuclear neutrophils are no longer considered as a homogeneous population of terminally differentiated and short-lived cells that belong to the innate immune system only. In fact, data from the past decades have uncovered that neutrophils exhibit large phenotypic heterogeneity and functional versatility that render them more plastic than previously thought. Hence, their precise role as effector cells in inflammation, in immune response and in other pathophysiological processes, including tumors, needs to be better evaluated. In such a complex scenario, common knowledge of the differentiation of neutrophils in bone marrow refers to lineage precursors, starting from the still poorly defined myeloblasts, and proceeding sequentially to promyelocytes, myelocytes, metamyelocytes, band cells, segmented neutrophils, and mature neutrophils, with each progenitor stage being more mature and better characterized. Thanks to the development and utilization of cutting-edge technologies, novel information about neutrophil precursors at stages earlier than the promyelocytes, hence closer to the hematopoietic stem cells, is emerging. Accordingly, this review discusses the main findings related to the very early precursors of human neutrophils and provides our perspectives on human neutropoiesis., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2023
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23. Neutrophils and their friends.
- Author
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Cassatella MA and Nauseef WM
- Subjects
- Humans, Neutrophils, Friends
- Published
- 2023
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24. CD14 + -Monocytes Exposed to Apolipoprotein CIII Express Tissue Factor.
- Author
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Olivieri O, Gasperini S, Calzetti F, Gardiman E, Castagna A, Martinelli N, Tamassia N, and Cassatella MA
- Subjects
- Humans, Apolipoprotein C-III metabolism, Apolipoproteins genetics, Apolipoproteins metabolism, RNA, Messenger metabolism, Monocytes metabolism, Thromboplastin genetics, Thromboplastin metabolism
- Abstract
Apolipoprotein CIII (ApoCIII) represents a key regulator of plasma lipid metabolism and a recognized risk factor for atherosclerosis and cardiovascular diseases. Beyond the regulation of lipoprotein trafficking, ApoCIII is also involved in endothelial dysfunction and monocyte recruitment related to atherothrombosis. With tissue factor (TF) being the primary initiator of the blood coagulation cascade, we hypothesized that ApoCIII-treated monocytes could express it. Hence, human CD14
+ -monocytes and autologous neutrophils were incubated with ApoCIII and sera from human subjects containing previously measured ApoCIII amounts. By RT-qPCR and ELISA, CD14+ -monocytes, but not neutrophils, were found to show increased mRNA expression and production of TNFα, IL-1β and IL-6 as well as TF mRNA once exposed to ultra-purified ApoCIII. By flow cytometry, CD14+ -monocytes were found to rapidly express TF on their cell surface membrane when incubated with either ApoCIII or sera with known concentrations of ApoCIII. Finally, preincubation with specific ApoCIII-neutralizing antibodies significantly reduced the ability of most sera with known concentrations of ApoCIII to upregulate TF protein, other than partially inhibiting cytokine release, in CD14+ -monocytes. In sum, herein we demonstrate that ApoCIII activates CD14+ -monocytes to express TF. The data identify a potential mechanism which links circulating apolipoproteins with inflammation and atherothrombosis-related processes underlying cardiovascular risk.- Published
- 2023
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25. SARS-CoV-2-Associated ssRNAs Activate Human Neutrophils in a TLR8-Dependent Fashion.
- Author
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Gardiman E, Bianchetto-Aguilera F, Gasperini S, Tiberio L, Scandola M, Lotti V, Gibellini D, Salvi V, Bosisio D, Cassatella MA, and Tamassia N
- Subjects
- Humans, COVID-19, Neutrophils metabolism, SARS-CoV-2 metabolism, Toll-Like Receptor 8 genetics, RNA, Viral genetics
- Abstract
COVID-19 disease is characterized by a dysregulation of the innate arm of the immune system. However, the mechanisms whereby innate immune cells, including neutrophils, become activated in patients are not completely understood. Recently, we showed that GU-rich RNA sequences from the SARS-CoV-2 genome (i.e., SCV2-RNA1 and SCV2-RNA2) activate dendritic cells. To clarify whether human neutrophils may also represent targets of SCV2-RNAs, neutrophils were treated with either SCV2-RNAs or, as a control, R848 (a TLR7/8 ligand), and were then analyzed for several functional assays and also subjected to RNA-seq experiments. Results highlight a remarkable response of neutrophils to SCV2-RNAs in terms of TNFα, IL-1ra, CXCL8 production, apoptosis delay, modulation of CD11b and CD62L expression, and release of neutrophil extracellular traps. By RNA-seq experiments, we observed that SCV2-RNA2 promotes a transcriptional reprogramming of neutrophils, characterized by the induction of thousands of proinflammatory genes, similar to that promoted by R848. Furthermore, by using CU-CPT9a, a TLR8-specific inhibitor, we found that SCV2-RNA2 stimulates neutrophils exclusively via TLR8-dependent pathways. In sum, our study proves that single-strand RNAs from the SARS-CoV-2 genome potently activate human neutrophils via TLR8, thus uncovering a potential mechanism whereby neutrophils may contribute to the pathogenesis of severe COVID-19 disease.
- Published
- 2022
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26. Neutrophils inhibit γδ T cell functions in the imiquimod-induced mouse model of psoriasis.
- Author
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Costa S, Bevilacqua D, Caveggion E, Gasperini S, Zenaro E, Pettinella F, Donini M, Dusi S, Constantin G, Lonardi S, Vermi W, De Sanctis F, Ugel S, Cestari T, Abram CL, Lowell CA, Rodegher P, Tagliaro F, Girolomoni G, Cassatella MA, and Scapini P
- Subjects
- Mice, Animals, Imiquimod, Neutrophils, NADP, Disease Models, Animal, NADPH Oxidases genetics, Disease Progression, Psoriasis chemically induced, Eczema
- Abstract
Background: Psoriasis is a chronic skin disease associated with deregulated interplays between immune cells and keratinocytes. Neutrophil accumulation in the skin is a histological feature that characterizes psoriasis. However, the role of neutrophils in psoriasis onset and development remains poorly understood., Methods: In this study, we utilized the model of psoriasiform dermatitis, caused by the repeated topical application of an imiquimod containing cream, in neutrophil-depleted mice or in mice carrying impairment in neutrophil functions, including p47phox -/- mice (lacking a cytosolic subunit of the phagocyte nicotinamide adenine dinucleotide phosphate - NADPH - oxidase) and Sykfl/fl MRP8-cre+ mice (carrying the specific deletion of the Syk kinase in neutrophils only), to elucidate the specific contribution of neutrophils to psoriasis development., Results: By analyzing disease development/progression in neutrophil-depleted mice, we now report that neutrophils act as negative modulators of disease propagation and exacerbation by inhibiting gammadelta T cell effector functions via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production. We also report that Syk functions as a crucial molecule in determining the outcome of neutrophil and γδ T cell interactions. Accordingly, we uncover that a selective impairment of Syk-dependent signaling in neutrophils is sufficient to reproduce the enhancement of skin inflammation and γδ T cell infiltration observed in neutrophil-depleted mice., Conclusions: Overall, our findings add new insights into the specific contribution of neutrophils to disease progression in the IMQ-induced mouse model of psoriasis, namely as negative regulatory cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Costa, Bevilacqua, Caveggion, Gasperini, Zenaro, Pettinella, Donini, Dusi, Constantin, Lonardi, Vermi, De Sanctis, Ugel, Cestari, Abram, Lowell, Rodegher, Tagliaro, Girolomoni, Cassatella and Scapini.)
- Published
- 2022
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27. Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress.
- Author
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Montaldo E, Lusito E, Bianchessi V, Caronni N, Scala S, Basso-Ricci L, Cantaffa C, Masserdotti A, Barilaro M, Barresi S, Genua M, Vittoria FM, Barbiera G, Lazarevic D, Messina C, Xue E, Marktel S, Tresoldi C, Milani R, Ronchi P, Gattillo S, Santoleri L, Di Micco R, Ditadi A, Belfiori G, Aleotti F, Naldini MM, Gentner B, Gardiman E, Tamassia N, Cassatella MA, Hidalgo A, Kwok I, Ng LG, Crippa S, Falconi M, Pettinella F, Scapini P, Naldini L, Ciceri F, Aiuti A, and Ostuni R
- Subjects
- Biomarkers metabolism, Humans, Interferons genetics, Interferons metabolism, Plastics metabolism, Myelopoiesis, Neutrophils metabolism
- Abstract
Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools., (© 2022. Springer Nature America, Inc.)
- Published
- 2022
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28. CD66b - CD64 dim CD115 - cells in the human bone marrow represent neutrophil-committed progenitors.
- Author
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Calzetti F, Finotti G, Tamassia N, Bianchetto-Aguilera F, Castellucci M, Canè S, Lonardi S, Cavallini C, Matte A, Gasperini S, Signoretto I, Benedetti F, Bonifacio M, Vermi W, Ugel S, Bronte V, Tecchio C, Scapini P, and Cassatella MA
- Subjects
- Bone Marrow Cells, COVID-19, GPI-Linked Proteins, Humans, Interferons, Antigens, CD, Bone Marrow, Cell Adhesion Molecules, Cell Differentiation, Neutrophils cytology, Receptor, Macrophage Colony-Stimulating Factor, Receptors, IgG
- Abstract
Here we report the identification of human CD66b
- CD64dim CD115- neutrophil-committed progenitor cells (NCPs) within the SSClo CD45dim CD34+ and CD34dim/- subsets in the bone marrow. NCPs were either CD45RA+ or CD45RA- , and in vitro experiments showed that CD45RA acquisition was not mandatory for their maturation process. NCPs exclusively generated human CD66b+ neutrophils in both in vitro differentiation and in vivo adoptive transfer experiments. Single-cell RNA-sequencing analysis indicated NCPs fell into four clusters, characterized by different maturation stages and distributed along two differentiation routes. One of the clusters was characterized by an interferon-stimulated gene signature, consistent with the reported expansion of peripheral mature neutrophil subsets that express interferon-stimulated genes in diseased individuals. Finally, comparison of transcriptomic and phenotypic profiles indicated NCPs represented earlier neutrophil precursors than the previously described early neutrophil progenitors (eNePs), proNeus and COVID-19 proNeus. Altogether, our data shed light on the very early phases of neutrophil ontogeny., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2022
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29. The PDE4 Inhibitor Tanimilast Restrains the Tissue-Damaging Properties of Human Neutrophils.
- Author
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Schioppa T, Nguyen HO, Salvi V, Maugeri N, Facchinetti F, Villetti G, Civelli M, Gaudenzi C, Passari M, Sozio F, Barbazza I, Tamassia N, Cassatella MA, Del Prete A, Bosisio D, and Tiberio L
- Subjects
- Cytokines metabolism, Endothelial Cells metabolism, Extracellular Traps metabolism, Humans, Phosphodiesterase 4 Inhibitors pharmacology, Phosphodiesterase 4 Inhibitors therapeutic use, Neutrophils drug effects, Neutrophils metabolism, Pulmonary Disease, Chronic Obstructive drug therapy, Pulmonary Disease, Chronic Obstructive pathology, Sulfonamides therapeutic use, para-Aminobenzoates therapeutic use
- Abstract
Neutrophils, the most abundant subset of leukocytes in the blood, play a pivotal role in host response against invading pathogens. However, in respiratory diseases, excessive infiltration and activation of neutrophils can lead to tissue damage. Tanimilast-international non-proprietary name of CHF6001-is a novel inhaled phosphodiesterase 4 (PDE4) inhibitor in advanced clinical development for the treatment of chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease where neutrophilic inflammation plays a key pathological role. Human neutrophils from healthy donors were exposed to pro-inflammatory stimuli in the presence or absence of tanimilast and budesonide-a typical inhaled corticosteroid drug-to investigate the modulation of effector functions including adherence to endothelial cells, granule protein exocytosis, release of extracellular DNA traps, cytokine secretion, and cell survival. Tanimilast significantly decreased neutrophil-endothelium adhesion, degranulation, extracellular DNA traps casting, and cytokine secretion. In contrast, it promoted neutrophil survival by decreasing both spontaneous apoptosis and cell death in the presence of pro-survival factors. The present work suggests that tanimilast can alleviate the severe tissue damage caused by massive recruitment and activation of neutrophils in inflammatory diseases such as COPD.
- Published
- 2022
- Full Text
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30. SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8.
- Author
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Salvi V, Nguyen HO, Sozio F, Schioppa T, Gaudenzi C, Laffranchi M, Scapini P, Passari M, Barbazza I, Tiberio L, Tamassia N, Garlanda C, Del Prete A, Cassatella MA, Mantovani A, Sozzani S, and Bosisio D
- Subjects
- COVID-19 genetics, COVID-19 immunology, Humans, Lung virology, SARS-CoV-2 immunology, COVID-19 virology, Immunity, Innate, RNA, Viral analysis, SARS-CoV-2 genetics, Toll-Like Receptor 7 immunology
- Abstract
The inflammatory and IFN pathways of innate immunity play a key role in the resistance and pathogenesis of coronavirus disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-associated molecular patterns (SAMPs) remain to be completely defined. Here, we identified single-stranded RNA (ssRNA) fragments from the SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and function, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream of these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identified TLR7/8 as a crucial cellular sensor of ssRNAs encoded by SARS-CoV-2 involved in host resistance and the disease pathogenesis of COVID-19.
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- 2021
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31. Anti-COVID-19 Vaccination in Patients with Autoimmune-Autoinflammatory Disorders and Primary/Secondary Immunodeficiencies: The Position of the Task Force on Behalf of the Italian Immunological Societies.
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D'Amelio R, Asero R, Cassatella MA, Laganà B, Lunardi C, Migliorini P, Nisini R, Parronchi P, Quinti I, Racanelli V, Senna G, Vacca A, and Maggi E
- Abstract
The Coronavirus disease 2019 (COVID-19) pandemic has represented an unprecedented challenge for humankind from health, economic, and social viewpoints. In February 2020, Italy was the first western country to be deeply hit by the pandemic and suffered the highest case/fatality rate among western countries. Brand new anti-COVID-19 vaccines have been developed and made available in <1-year from the viral sequence publication. Patients with compromised immune systems, such as autoimmune-autoinflammatory disorders (AIAIDs), primary (PIDs) and secondary (SIDs) immunodeficiencies, have received careful attention for a long time regarding their capacity to safely respond to traditional vaccines. The Italian Immunological Societies, therefore, have promptly faced the issues of safety, immunogenicity, and efficacy/effectiveness of the innovative COVID-19 vaccines, as well as priority to vaccine access, in patients with AIADs, PIDs, and SIDs, by organizing an ad-hoc Task Force. Patients with AIADs, PIDs, and SIDs: (1) Do not present contraindications to COVID-19 vaccines if a mRNA vaccine is used and administered in a stabilized disease phase without active infection. (2) Should usually not discontinue immunosuppressive therapy, which may be modulated depending on the patient's clinical condition. (3) When eligible, should have a priority access to vaccination. In fact, immunizing these patients may have relevant social/health consequences, since these patients, if infected, may develop chronic infection, which prolongs viral spread and facilitates the emergence of viral variants.
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- 2021
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32. Characterizing the Complexities of Neutrophils with Suppressive Properties.
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Cassatella MA
- Subjects
- Humans, T-Lymphocytes, Neoplasms, Neutrophils
- Abstract
Several not-yet fully described neutrophil populations exerting either antitumor or suppressive/protumor functions may appear in the circulation of patients with cancer and/or infiltrate tumor tissues. In this issue, Emmons and colleagues provide new information on how complement-dependent "activation" of normal mature neutrophils renders the cells able to inhibit T-cell responsiveness in vitro The data highlight the complexities of understanding the biology of neutrophil-mediated T-cell suppression. See related article by Emmons et al., p. 790., (©2021 American Association for Cancer Research.)
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- 2021
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33. Induction of OCT2 contributes to regulate the gene expression program in human neutrophils activated via TLR8.
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Tamassia N, Bianchetto-Aguilera F, Gasperini S, Polletti S, Gardiman E, Ostuni R, Natoli G, and Cassatella MA
- Subjects
- Humans, Gene Expression Profiling methods, Neutrophil Activation genetics, Organic Cation Transporter 2 metabolism, Toll-Like Receptor 8 metabolism
- Abstract
The transcription factors (TFs) that regulate inducible genes in activated neutrophils are not yet completely characterized. Herein, we show that the genomic distribution of the histone modification H3K27Ac, as well as PU.1 and C/EBPβ, two myeloid-lineage-determining TFs (LDTFs), significantly changes in human neutrophils treated with R848, a ligand of Toll-like receptor 8 (TLR8). Interestingly, differentially acetylated and LDTF-marked regions reveal an over-representation of OCT-binding motifs that are selectively bound by OCT2/POU2F2. Analysis of OCT2 genomic distribution in primary neutrophils and of OCT2-depletion in HL-60-differentiated neutrophils proves the requirement for OCT2 in contributing to promote, along with nuclear factor κB (NF-κB) and activator protein 1 (AP-1), the TLR8-induced gene expression program in neutrophils. Altogether, our data demonstrate that neutrophils, upon activation via TLR8, profoundly reprogram their chromatin status, ultimately displaying cell-specific, prolonged transcriptome changes. Data also show an unexpected role for OCT2 in amplifying the transcriptional response to TLR8-mediated activation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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34. Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation.
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Tecchio C and Cassatella MA
- Subjects
- Animals, Graft vs Host Disease prevention & control, Hematologic Neoplasms pathology, Humans, Graft vs Host Disease immunology, Hematologic Neoplasms immunology, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation methods, Neutrophils immunology
- Abstract
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT.
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- 2021
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35. Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome.
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Caldarale F, Giacomelli M, Garrafa E, Tamassia N, Morreale A, Poli P, Timpano S, Baresi G, Zunica F, Cattalini M, Moratto D, Chiarini M, Cannizzo ES, Marchetti G, Cassatella MA, Taddio A, Tommasini A, and Badolato R
- Subjects
- Child, Child, Preschool, Female, Humans, Infant, Male, Retrospective Studies, COVID-19 immunology, Chemokine CXCL10 immunology, Chemokine CXCL9 immunology, Dendritic Cells immunology, Interferon-gamma immunology, Plasma Cells immunology, SARS-CoV-2 immunology, Systemic Inflammatory Response Syndrome immunology
- Abstract
Background: SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD)., Objective: With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations., Methods: We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission., Results: Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19., Conclusions: Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Caldarale, Giacomelli, Garrafa, Tamassia, Morreale, Poli, Timpano, Baresi, Zunica, Cattalini, Moratto, Chiarini, Cannizzo, Marchetti, Cassatella, Taddio, Tommasini and Badolato.)
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- 2021
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36. Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.
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Lonardi S, Missale F, Calza S, Bugatti M, Vescovi R, Debora B, Uppaluri R, Egloff AM, Mattavelli D, Lombardi D, Benerini Gatta L, Marini O, Tamassia N, Gardiman E, Cassatella MA, Scapini P, Nicolai P, and Vermi W
- Abstract
Objectives: The role of tumor-associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs., Methods: The relevance, derivation, phenotype and interactions of nodal TANs were explored via a large immunohistochemical analysis of carcinoma-draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor-promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial-to-mesenchymal transition (EMT) signatures., Results: The pan-carcinoma screening identified a consistent infiltration (59%) of CD66b
+ TANs in tumor-draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra-lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. In vitro experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM-CSF. Moreover, by retrospective analysis, a high CD66b+ TAN density in M-TDLNs of OSCC ( n = 182 patients) predicted a worse prognosis. The analysis of the OSCC-TCGA dataset unveiled that the expression of a set of neutrophil-specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66b+ TANs co-localised with PDPN+ S100A9- EMT-switched tumor cells in areas of lymphangiogenesis. The pro-EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs., Conclusion: Our findings are consistent with a novel pro-tumoral TAN compartment that may promote nodal spread via EMT, through the lymphatics., Competing Interests: The authors declare no competing financial interests., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
- 2021
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37. Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma.
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Russignan A, Dal Collo G, Bagnato A, Tamassia N, Bugatti M, Belleri M, Lorenzi L, Borsi E, Bazzoni R, Gottardi M, Terragna C, Vermi W, Giacomini A, Presta M, Cassatella MA, Krampera M, and Tecchio C
- Abstract
The endothelin-1 (ET-1) receptors were recently found to mediate pro-survival functions in multiple myeloma (MM) cells in response to autocrine ET-1. This study investigated the effectiveness of macitentan, a dual ET-1 receptor antagonist, in MM treatment, and the mechanisms underlying its activities. Macitentan affected significantly MM cell (RPMI-8226, U266, KMS-12-PE) survival and pro-angiogenic cytokine release by down-modulating ET-1-activated MAPK/ERK and HIF-1α pathways, respectively. HIF-1α silencing abrogated the ET-1 mediated induction of genes encoding for pro-angiogenic cytokines such as VEGF-A, IL-8, Adrenomedullin, and ET-1 itself. Upon exposure to macitentan, MM cells cultured in the presence of the hypoxia-mimetic agent CoCl
2 , exogenous ET-1, or CoCl2 plus ET-1, down-regulated HIF-1α and the transcription and release of downstream pro-angiogenic cytokines. Consistently, macitentan limited significantly the basal pro-angiogenic activity of RPMI-8226 cells in chorioallantoic membrane assay. In xenograft mouse models, established by injecting NOG mice either via intra-caudal vein with U266 or subcutaneously with RPMI-8226 cells, macitentan reduced effectively the number of MM cells infiltrating bone marrow, and the size and microvascular density of subcutaneous MM tumors. ET-1 receptors targeting by macitentan represents an effective anti-proliferative and anti-angiogenic therapeutic approach in preclinical settings of MM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Russignan, Dal Collo, Bagnato, Tamassia, Bugatti, Belleri, Lorenzi, Borsi, Bazzoni, Gottardi, Terragna, Vermi, Giacomini, Presta, Cassatella, Krampera and Tecchio.)- Published
- 2021
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38. On the Improper Use of the Term High-Density Neutrophils.
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Cassatella MA and Scapini P
- Subjects
- Cell Count, Humans, Neutrophils cytology, Terminology as Topic
- Abstract
Recent studies have revealed that neutrophils exhibit an unsuspected heterogeneity. In this context, the term high-density neutrophils (HDNs) has recently gained ground to define nothing more than neutrophils displaying an unaltered normal density. Therefore, as discussed here, we argue that the HDNs term must be avoided, as it is confounding and scientifically inappropriate., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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39. Human neutrophils activated by TLR8 agonists, with or without IFNγ, synthesize and release EBI3, but not IL-12, IL-27, IL-35, or IL-39.
- Author
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Cassatella MA, Gardiman E, Arruda-Silva F, Bianchetto-Aguilera F, Gasperini S, Bugatti M, Vermi W, Larousserie F, Devergne O, and Tamassia N
- Subjects
- Animals, Humans, Interferon-gamma immunology, Interleukin-12 immunology, Interleukins immunology, Mice, Minor Histocompatibility Antigens immunology, Neutrophils pathology, Toll-Like Receptor 8 immunology, Imidazoles pharmacology, Neutrophils immunology, Toll-Like Receptor 8 agonists
- Abstract
The IL-12 family of cytokines plays crucial functions in innate and adaptive immunity. These cytokines include heterodimers sharing distinct α (IL-12A, IL-23A, and IL-27A) with two β (IL-12B and Epstein-Barr virus induced gene 3 [EBI3]) chains, respectively, IL-12 (IL-12B plus IL-12A) and IL-23 (IL-12B plus IL-23A) sharing IL-12B, IL-27 (EBI3 plus IL-27A), IL-35 (EBI3 plus IL-12A), and IL-39 (EBI3 plus IL-23A) sharing EBI3. In this context, we have recently reported that highly pure neutrophils incubated with TLR8 agonists produce functional IL-23. Previously, we showed that neutrophils incubated with LPS plus IFNγ for 20 h produce IL-12. Herein, we investigated whether highly pure, TLR8-activated, neutrophils produce EBI3, and in turn IL-27, IL-35, and IL-39, the IL-12 members containing it. We report that neutrophils incubated with TLR8 ligands, TNFα and, to a lesser extent, LPS, produce and release remarkable amounts of EBI3, but not IL-27A, consequently excluding the possibility for an IL-27 production. We also report a series of unsuccessful experiments performed to investigate whether neutrophil-derived EBI3 associates with IL-23A to form IL-39. Furthermore, we show that neutrophils incubated with IFNγ in combination with either TLR8 or TLR4 ligands express/produce neither IL-12, nor IL-35, due to the inability of IFNγ, contrary to previous findings, to activate IL12A transcription. Even IL-27 was undetectable in supernatants harvested from IFNγ plus R848-treated neutrophils, although they were found to accumulate IL27A transcripts. Finally, by immunohistochemistry experiments, EBI3-positive neutrophils were found in discrete pathologies only, including diverticulitis, cholecystitis, Gorham disease, and Bartonella Henselae infection, implying a specific role of neutrophil-derived EBI3 in vivo., (©2020 Society for Leukocyte Biology.)
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- 2020
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40. The global response to the COVID-19 pandemic: how have immunology societies contributed?
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Osier F, Ting JPY, Fraser J, Lambrecht BN, Romano M, Gazzinelli RT, Bortoluci KR, Zamboni DS, Akbar AN, Evans J, Brown DE, Patel KD, Wu Y, Perez AB, Pérez O, Kamradt T, Falk C, Barda-Saad M, Ariel A, Santoni A, Annunziato F, Cassatella MA, Kiyono H, Chereshnev V, Dieye A, Mbow M, Mbengue B, Niang MDS, and Suchard M
- Subjects
- Antiviral Agents chemical synthesis, Antiviral Agents therapeutic use, Betacoronavirus drug effects, Betacoronavirus immunology, Betacoronavirus pathogenicity, COVID-19 immunology, COVID-19 prevention & control, COVID-19 therapy, COVID-19 Vaccines, Community-Institutional Relations, Coronavirus Infections immunology, Coronavirus Infections prevention & control, Coronavirus Infections therapy, Global Health trends, Humans, Patient Education as Topic organization & administration, Personal Protective Equipment supply & distribution, Pneumonia, Viral immunology, Pneumonia, Viral therapy, SARS-CoV-2, Severe Acute Respiratory Syndrome immunology, Severe Acute Respiratory Syndrome therapy, Viral Vaccines biosynthesis, COVID-19 epidemiology, Coronavirus Infections epidemiology, International Cooperation, Pandemics, Pneumonia, Viral epidemiology, Severe Acute Respiratory Syndrome epidemiology, Societies, Scientific organization & administration
- Abstract
The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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- 2020
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41. Deciphering the fate of slan + -monocytes in human tonsils by gene expression profiling.
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Bianchetto-Aguilera F, Tamassia N, Gasperini S, Calzetti F, Finotti G, Gardiman E, Montioli R, Bresciani D, Vermi W, and Cassatella MA
- Subjects
- Case-Control Studies, Cells, Cultured, Dendritic Cells cytology, Gene Expression Profiling, Humans, Macrophages cytology, Monocytes cytology, Palatine Tonsil cytology, Tonsillitis metabolism, Tonsillitis pathology, Amino Sugars metabolism, Dendritic Cells metabolism, Macrophages metabolism, Monocytes metabolism, Palatine Tonsil metabolism, Tonsillitis genetics
- Abstract
Monocytic cells perform crucial homeostatic and defensive functions. However, their fate and characterization at the transcriptomic level in human tissues are partially understood, often as a consequence of the lack of specific markers allowing their unequivocal identification. The 6-sulfo LacNAc (slan) antigen identifies a subset of non-classical (NC) monocytes in the bloodstream, namely the slan
+ -monocytes. In recent studies, we and other groups have reported that, in tonsils, slan marks dendritic cell (DC)-like cells, as defined by morphological, phenotypical, and functional criteria. However, subsequent investigations in lymphomas have uncovered a significant heterogeneity of tumor-infiltrating slan+ -cells, including a macrophage-like state. Based on their emerging role in tissue inflammation and cancer, herein we investigated slan+ -cell fate in tonsils by using a molecular-based approach. Hence, RNA from tonsil slan+ -cells, conventional CD1c+ DCs (cDC2) and CD11b+ CD14+ -macrophages was subjected to gene expression analysis. For comparison, transcriptomes were also obtained from blood cDC2, classical (CL), intermediate (INT), NC, and slan+ -monocytes. Data demonstrate that the main trajectory of human slan+ -monocytes infiltrating the tonsil tissue is toward a macrophage-like population, displaying molecular features distinct from those of tonsil CD11b+ CD14+ -macrophages and cDC2. These findings provide a novel view on the terminal differentiation path of slan+ -monocytes, which is relevant for inflammatory diseases and lymphomas., (© 2020 Federation of American Societies for Experimental Biology.)- Published
- 2020
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42. CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis.
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Lonardi S, Scutera S, Licini S, Lorenzi L, Cesinaro AM, Gatta LB, Castagnoli C, Bollero D, Sparti R, Tomaselli M, Medicina D, Calzetti F, Cassatella MA, Facchetti F, Musso T, and Vermi W
- Subjects
- Adolescent, Adult, Aged, Apoptosis, Cell Lineage, Cells, Cultured, Child, Child, Preschool, Dendritic Cells metabolism, Female, Histiocytosis, Langerhans-Cell metabolism, Humans, Infant, Infant, Newborn, Langerhans Cells metabolism, Male, Middle Aged, Monocytes metabolism, Tumor Microenvironment, Young Adult, Cell Differentiation, Cell Movement, Dendritic Cells pathology, Histiocytosis, Langerhans-Cell pathology, Langerhans Cells pathology, Monocytes pathology, Receptor, Macrophage Colony-Stimulating Factor metabolism
- Abstract
Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1a
+ CD207+ LCH cells. In LCH, somatic mutations of the BRAFV600E gene have been detected in tissue LCH cells, bone marrow CD34+ hematopoietic stem cells, circulating CD14+ monocytes, and BDCA1+ myeloid dendritic cells (DC). Targeting BRAFV600E in clonal Langerhans cells (LC) and their precursors is a potential treatment option for patients whose tumors have the mutation. The development of mouse macrophages and LCs is regulated by the CSF1 receptor (CSF1R). In patients with diffuse-type tenosynovial giant cell tumors, CSF1R inhibition depletes tumor-associated macrophages (TAM) with therapeutic efficacy; however, CSF1R signaling in LCs and LCH has not been investigated. We found through IHC and flow cytometry that CSF1R is normally expressed on human CD1a+ CD207+ LCs in the epidermis and stratified epithelia. LCs that were differentiated from CD14+ monocytes, BDCA1+ DCs, and CD34+ cord blood progenitors expressed CSF1R that was downregulated upon maturation. Immature LCs migrated toward CSF1, but not IL34. Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. In LCH clinical samples, LCH cells (including BRAFV600E cells) and TAMs retained high expression of CSF1R. We also detected the presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAFV600E and wild-type forms of the disease., (©2020 American Association for Cancer Research.)- Published
- 2020
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43. Editorial: Neutrophil Communication.
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Knight JS, Jain R, Cassatella MA, and Lood C
- Subjects
- Animals, Cell Communication, Cytokines metabolism, Humans, Immunity, Neutrophil Activation, Phagocytosis, Reactive Oxygen Species metabolism, Extracellular Traps metabolism, Inflammation immunology, Neutrophils immunology
- Published
- 2020
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44. Fast and Accurate Quantitative Analysis of Cytokine Gene Expression in Human Neutrophils by Reverse Transcription Real-Time PCR.
- Author
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Tamassia N, Cassatella MA, and Bazzoni F
- Subjects
- Cytokines metabolism, Humans, Neutrophil Activation genetics, Neutrophil Activation immunology, RNA, Messenger genetics, RNA, Messenger isolation & purification, Cytokines genetics, Gene Expression, Neutrophils immunology, Neutrophils metabolism, Real-Time Polymerase Chain Reaction methods, Reverse Transcriptase Polymerase Chain Reaction methods
- Abstract
Polymorphonuclear neutrophils, traditionally viewed as short-lived effector cells, are nowadays regarded as important components of effector and regulatory circuits in the innate and adaptive immune systems. Most of the physiological functions of neutrophils as crucial players in the host immune response, able not only to act in the early phases of acute inflammation but also to condition the progression of the inflammatory reaction and the subsequent initiation of the specific immune response, relies on their capacity to produce and release a number of proinflammatory and immunoregulatory cytokines. This fact has reevaluated the importance, the role, and the physiological and pathological significance of neutrophils in the pathogenesis of inflammatory, infectious, autoimmune, and neoplastic diseases and has identified neutrophils as an important potential target for selective pharmacological intervention to both promote and restrain inflammation. In this context, understanding the mechanisms of modulation of neutrophil-derived cytokines and chemokines represents a critical step toward a better understanding of how neutrophils may influence pathophysiological processes in vivo. Herein, we describe and discuss an updated version of the methods that we have developed to rapidly and precisely characterize the pattern of cytokine expression in in vitro-activated human neutrophils. The validation of the reverse transcription quantitative real-time PCR assay as a suitable strategy for an accurate, sensitive, reliable, and bona fide analysis of cytokine gene expression in human neutrophils overcomes several problems strictly specific to neutrophils and offers an important tool, in the neutrophil research area, to test many experimental conditions for gene expression analysis.
- Published
- 2020
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45. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).
- Author
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Cossarizza A, Chang HD, Radbruch A, Acs A, Adam D, Adam-Klages S, Agace WW, Aghaeepour N, Akdis M, Allez M, Almeida LN, Alvisi G, Anderson G, Andrä I, Annunziato F, Anselmo A, Bacher P, Baldari CT, Bari S, Barnaba V, Barros-Martins J, Battistini L, Bauer W, Baumgart S, Baumgarth N, Baumjohann D, Baying B, Bebawy M, Becher B, Beisker W, Benes V, Beyaert R, Blanco A, Boardman DA, Bogdan C, Borger JG, Borsellino G, Boulais PE, Bradford JA, Brenner D, Brinkman RR, Brooks AES, Busch DH, Büscher M, Bushnell TP, Calzetti F, Cameron G, Cammarata I, Cao X, Cardell SL, Casola S, Cassatella MA, Cavani A, Celada A, Chatenoud L, Chattopadhyay PK, Chow S, Christakou E, Čičin-Šain L, Clerici M, Colombo FS, Cook L, Cooke A, Cooper AM, Corbett AJ, Cosma A, Cosmi L, Coulie PG, Cumano A, Cvetkovic L, Dang VD, Dang-Heine C, Davey MS, Davies D, De Biasi S, Del Zotto G, Dela Cruz GV, Delacher M, Della Bella S, Dellabona P, Deniz G, Dessing M, Di Santo JP, Diefenbach A, Dieli F, Dolf A, Dörner T, Dress RJ, Dudziak D, Dustin M, Dutertre CA, Ebner F, Eckle SBG, Edinger M, Eede P, Ehrhardt GRA, Eich M, Engel P, Engelhardt B, Erdei A, Esser C, Everts B, Evrard M, Falk CS, Fehniger TA, Felipo-Benavent M, Ferry H, Feuerer M, Filby A, Filkor K, Fillatreau S, Follo M, Förster I, Foster J, Foulds GA, Frehse B, Frenette PS, Frischbutter S, Fritzsche W, Galbraith DW, Gangaev A, Garbi N, Gaudilliere B, Gazzinelli RT, Geginat J, Gerner W, Gherardin NA, Ghoreschi K, Gibellini L, Ginhoux F, Goda K, Godfrey DI, Goettlinger C, González-Navajas JM, Goodyear CS, Gori A, Grogan JL, Grummitt D, Grützkau A, Haftmann C, Hahn J, Hammad H, Hämmerling G, Hansmann L, Hansson G, Harpur CM, Hartmann S, Hauser A, Hauser AE, Haviland DL, Hedley D, Hernández DC, Herrera G, Herrmann M, Hess C, Höfer T, Hoffmann P, Hogquist K, Holland T, Höllt T, Holmdahl R, Hombrink P, Houston JP, Hoyer BF, Huang B, Huang FP, Huber JE, Huehn J, Hundemer M, Hunter CA, Hwang WYK, Iannone A, Ingelfinger F, Ivison SM, Jäck HM, Jani PK, Jávega B, Jonjic S, Kaiser T, Kalina T, Kamradt T, Kaufmann SHE, Keller B, Ketelaars SLC, Khalilnezhad A, Khan S, Kisielow J, Klenerman P, Knopf J, Koay HF, Kobow K, Kolls JK, Kong WT, Kopf M, Korn T, Kriegsmann K, Kristyanto H, Kroneis T, Krueger A, Kühne J, Kukat C, Kunkel D, Kunze-Schumacher H, Kurosaki T, Kurts C, Kvistborg P, Kwok I, Landry J, Lantz O, Lanuti P, LaRosa F, Lehuen A, LeibundGut-Landmann S, Leipold MD, Leung LYT, Levings MK, Lino AC, Liotta F, Litwin V, Liu Y, Ljunggren HG, Lohoff M, Lombardi G, Lopez L, López-Botet M, Lovett-Racke AE, Lubberts E, Luche H, Ludewig B, Lugli E, Lunemann S, Maecker HT, Maggi L, Maguire O, Mair F, Mair KH, Mantovani A, Manz RA, Marshall AJ, Martínez-Romero A, Martrus G, Marventano I, Maslinski W, Matarese G, Mattioli AV, Maueröder C, Mazzoni A, McCluskey J, McGrath M, McGuire HM, McInnes IB, Mei HE, Melchers F, Melzer S, Mielenz D, Miller SD, Mills KHG, Minderman H, Mjösberg J, Moore J, Moran B, Moretta L, Mosmann TR, Müller S, Multhoff G, Muñoz LE, Münz C, Nakayama T, Nasi M, Neumann K, Ng LG, Niedobitek A, Nourshargh S, Núñez G, O'Connor JE, Ochel A, Oja A, Ordonez D, Orfao A, Orlowski-Oliver E, Ouyang W, Oxenius A, Palankar R, Panse I, Pattanapanyasat K, Paulsen M, Pavlinic D, Penter L, Peterson P, Peth C, Petriz J, Piancone F, Pickl WF, Piconese S, Pinti M, Pockley AG, Podolska MJ, Poon Z, Pracht K, Prinz I, Pucillo CEM, Quataert SA, Quatrini L, Quinn KM, Radbruch H, Radstake TRDJ, Rahmig S, Rahn HP, Rajwa B, Ravichandran G, Raz Y, Rebhahn JA, Recktenwald D, Reimer D, Reis e Sousa C, Remmerswaal EBM, Richter L, Rico LG, Riddell A, Rieger AM, Robinson JP, Romagnani C, Rubartelli A, Ruland J, Saalmüller A, Saeys Y, Saito T, Sakaguchi S, Sala-de-Oyanguren F, Samstag Y, Sanderson S, Sandrock I, Santoni A, Sanz RB, Saresella M, Sautes-Fridman C, Sawitzki B, Schadt L, Scheffold A, Scherer HU, Schiemann M, Schildberg FA, Schimisky E, Schlitzer A, Schlosser J, Schmid S, Schmitt S, Schober K, Schraivogel D, Schuh W, Schüler T, Schulte R, Schulz AR, Schulz SR, Scottá C, Scott-Algara D, Sester DP, Shankey TV, Silva-Santos B, Simon AK, Sitnik KM, Sozzani S, Speiser DE, Spidlen J, Stahlberg A, Stall AM, Stanley N, Stark R, Stehle C, Steinmetz T, Stockinger H, Takahama Y, Takeda K, Tan L, Tárnok A, Tiegs G, Toldi G, Tornack J, Traggiai E, Trebak M, Tree TIM, Trotter J, Trowsdale J, Tsoumakidou M, Ulrich H, Urbanczyk S, van de Veen W, van den Broek M, van der Pol E, Van Gassen S, Van Isterdael G, van Lier RAW, Veldhoen M, Vento-Asturias S, Vieira P, Voehringer D, Volk HD, von Borstel A, von Volkmann K, Waisman A, Walker RV, Wallace PK, Wang SA, Wang XM, Ward MD, Ward-Hartstonge KA, Warnatz K, Warnes G, Warth S, Waskow C, Watson JV, Watzl C, Wegener L, Weisenburger T, Wiedemann A, Wienands J, Wilharm A, Wilkinson RJ, Willimsky G, Wing JB, Winkelmann R, Winkler TH, Wirz OF, Wong A, Wurst P, Yang JHM, Yang J, Yazdanbakhsh M, Yu L, Yue A, Zhang H, Zhao Y, Ziegler SM, Zielinski C, Zimmermann J, and Zychlinsky A
- Subjects
- Consensus, Humans, Phenotype, Allergy and Immunology standards, Cell Separation methods, Cell Separation standards, Flow Cytometry methods, Flow Cytometry standards
- Abstract
These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2019
- Full Text
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46. 6-Sulfo LacNAc (Slan) as a Marker for Non-classical Monocytes.
- Author
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Hofer TP, van de Loosdrecht AA, Stahl-Hennig C, Cassatella MA, and Ziegler-Heitbrock L
- Subjects
- Animals, Humans, Phenotype, Amino Sugars metabolism, Biomarkers metabolism, Dendritic Cells immunology, Inflammation immunology, Monocytes immunology, Neoplasms immunology
- Abstract
Monocytes are subdivided into three subsets, which have different phenotypic and functional characteristics and different roles in inflammation and malignancy. When in man CD14 and CD16 monoclonal antibodies are used to define these subsets, then the distinction of non-classical CD14low and intermediate CD14high monocytes requires setting a gate in what is a gradually changing level of CD14 expression. In the search for an additional marker to better dissect the two subsets we have explored the marker 6-sulfo LacNAc (slan). Slan is a carbohydrate residue originally described to be expressed on the cell surface of a type of dendritic cell in human blood. We elaborate herein that the features of slan+ cells are congruent with the features of CD16+ non-classical monocytes and that slan is a candidate marker for definition of non-classical monocytes. The use of this marker may help in studying the role of non-classical monocytes in health and in diagnosis and monitoring of disease., (Copyright © 2019 Hofer, van de Loosdrecht, Stahl-Hennig, Cassatella and Ziegler-Heitbrock.)
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- 2019
- Full Text
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47. IL-10-producing B cells are characterized by a specific methylation signature.
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Tonon S, Mion F, Dong J, Chang HD, Dalla E, Scapini P, Perruolo G, Zanello A, Dugo M, Cassatella MA, Colombo MP, Radbruch A, Tripodo C, and Pucillo CE
- Subjects
- Animals, Cell Differentiation, DNA Methylation, Female, Gene Expression Profiling, Humans, Immune Tolerance, Immunity, Humoral, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Tumor Microenvironment, B-Lymphocyte Subsets physiology, B-Lymphocytes, Regulatory physiology, Interleukin-10 metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Mantle-Cell genetics, Regulatory Sequences, Nucleic Acid genetics
- Abstract
Among the family of regulatory B cells, the subset able to produce interleukin-10 (IL-10) is the most studied, yet its biology is still a matter of investigation. The DNA methylation profiling of the il-10 gene locus revealed a novel epigenetic signature characterizing murine B cells ready to respond through IL-10 synthesis: a demethylated region located 4.5 kb from the transcription starting site (TSS), that we named early IL10 regulatory region (eIL10rr). This feature allows to distinguish B cells that are immediately prone and developmentally committed to IL-10 production from those that require a persistent stimulation to exert an IL-10-mediated regulatory function. These late IL-10 producers are instead characterized by a delayed IL10 regulatory region (dIL10rr), a partially demethylated DNA portion located 9 kb upstream from the TSS. A demethylated region was also found in human IL-10-producing B cells and, very interestingly, in some B-cell malignancies, such as chronic lymphocytic leukemia and mantle cell lymphoma, characterized by an immunosuppressive microenvironment. Our findings define murine and human regulatory B cells as an epigenetically controlled functional state of mature B cell subsets and open a new perspective on IL-10 regulation in B cells in homeostasis and disease., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2019
- Full Text
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48. Multisystem autoimmune disease caused by increased STAT3 phosphorylation and dysregulated gene expression.
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Todaro F, Tamassia N, Pinelli M, Moratto D, Dotta L, Grassi A, Consonni F, Giacomelli M, Lionetti P, Gardiman E, Cassatella MA, Gambineri E, Canani RB, and Badolato R
- Subjects
- Autoimmune Diseases metabolism, Autoimmune Diseases pathology, Child, Humans, Male, Multiple Organ Failure metabolism, Multiple Organ Failure pathology, Mutation, Phosphorylation, Prognosis, STAT3 Transcription Factor genetics, Autoimmune Diseases etiology, Gene Expression Regulation, Multiple Organ Failure etiology, STAT3 Transcription Factor metabolism
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- 2019
- Full Text
- View/download PDF
49. Biological Roles of Neutrophil-Derived Granule Proteins and Cytokines.
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Cassatella MA, Östberg NK, Tamassia N, and Soehnlein O
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- Animals, Disease Susceptibility, Hematopoiesis, Humans, Myelopoiesis, Neutrophils pathology, Proteome, Proteomics methods, Cytokines metabolism, Cytoplasmic Granules metabolism, Neutrophils immunology, Neutrophils metabolism, Proteostasis
- Abstract
Neutrophils, the most abundant white blood cells in human circulation, entertain intense interactions with other leukocyte subsets, platelets, and stromal cells. Molecularly, such interactions are typically communicated through proteins generated during granulopoiesis, stored in granules, or produced on demand. Here, we provide an overview of the mammalian regulation of granule protein production in the bone marrow and the de novo synthesis of cytokines by neutrophils recruited to tissues. In addition, we discuss some of the known biological roles of these protein messengers, and how neutrophil-borne granule proteins and cytokines can synergize to modulate inflammation and tumor development. Decoding the neutrophil interactome is important for therapeutically neutralizing individual proteins to putatively dampen inflammation, or for delivering modified neutrophil-borne proteins to boost host defense., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2019
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50. Human neutrophils activated via TLR8 promote Th17 polarization through IL-23.
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Tamassia N, Arruda-Silva F, Wright HL, Moots RJ, Gardiman E, Bianchetto-Aguilera F, Gasperini S, Capone M, Maggi L, Annunziato F, Edwards SW, and Cassatella MA
- Subjects
- Humans, Monocytes cytology, Monocytes immunology, Neutrophils cytology, Th17 Cells immunology, Toll-Like Receptor 8 agonists, Tumor Necrosis Factor-alpha immunology, Interleukin-12 Subunit p40 immunology, Interleukin-23 Subunit p19 immunology, Neutrophil Activation, Neutrophils immunology, Toll-Like Receptor 8 immunology
- Abstract
Human neutrophils contribute to the regulation of inflammation via the generation of a range of cytokines that affect all elements of the immune system. Here, we investigated their ability to express some of the members of the IL-12 family after incubation with TLR8 agonists. Highly pure human neutrophils were thus incubated for up to 48 h with or without R848, or other TLR8 agonists, to then measure the expression levels of transcripts and proteins for IL-12 family member subunits by RNA-seq, reverse transcription quantitative PCR, and ELISA. We show a TLR8-mediated inducible expression of IL-12B and IL-23A, but not IL-12A, mRNA, which occurs via chromatin remodeling (as assessed by ChIP-seq), and subsequent production of IL-23 and IL-12B, but no IL-12, proteins. Induction of IL-23 requires endogenous TNF-α, as both mRNA and protein levels were blocked in TLR8-activated neutrophils via a TNF-α-neutralizing Ab. We also show that supernatants from TLR8-activated neutrophils, but not autologous monocytes, induce the differentiation of Th17 cells from naïve T cells in an IL-23-dependent fashion. This study unequivocally demonstrates that highly pure human neutrophils express and produce IL-23, further supporting the key roles played by these cells in the important IL-17/IL-23 network and Th17 responses., (©2019 Society for Leukocyte Biology.)
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- 2019
- Full Text
- View/download PDF
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