36 results on '"Curato, C"'
Search Results
2. Cardioprotective roles of estrogen receptors via bone marrow c-kit+ precursor cells: OP119
- Author
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Slavic, S, Curato, C, Altarche-Xifro, W, Timm, M, Kappert, K, Unger, T, and Li, J
- Published
- 2009
3. Differentiation of cardiac c-kit+AT2+ cells into various lineages in vitro: OP004
- Author
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Altarche-Xifró, W, Curato, C, Slavic1, S, Skorska1, A, Kappert1, K, Steckelings, M, Unger, T, and Li, J
- Published
- 2009
4. ERa is expressed in cardiac stem cells and supports self-renewal after cardiac ischemic injury in rat: OP59
- Author
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Brinckmann, M, Timm, M, Kaschina, E, Grzesiak, A, Curato, C, Unger, T, and Li, J
- Published
- 2007
5. TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine
- Author
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Pascual-Reguant, A., primary, Bayat Sarmadi, J., additional, Baumann, C., additional, Noster, R., additional, Cirera-Salinas, D., additional, Curato, C., additional, Pelczar, P., additional, Huber, S., additional, Zielinski, C.E., additional, Löhning, M., additional, Hauser, A.E., additional, and Esplugues, E., additional
- Published
- 2017
- Full Text
- View/download PDF
6. Identification and characterization of the CD4+AT2R+ T cell subpo-pulation in rats and humans
- Author
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Skorska A, Curato C, Wassim Altarche Xifro, Slavic S, Unger T, Steinhoff G, and Li J
- Published
- 2014
7. Nanotechnology-based immunotherapeutic approach for tumour eradication
- Author
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Zupančič, E., primary, Curato, C., additional, Eisenbach, L., additional, Jung, S., additional, and Florindo, H., additional
- Published
- 2016
- Full Text
- View/download PDF
8. 3rd EACTS Meeting on Cardiac and Pulmonary Regeneration Berlin-Brandenburgische Akademie, Berlin, Germany, 14-15 December 2012
- Author
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Bader, A, Brodarac, A, Hetzer, R, Kurtz, A, Stamm, C, Baraki, H, Kensah, G, Asch, S, Rojas, S, Martens, A, Gruh, I, Haverich, A, Kutschka, I, Cortes Dericks, L, Froment, L, Kocher, G, Schmid, Ra, Delyagina, E, Schade, A, Scharfenberg, D, Skorska, A, Lux, C, Li, W, Steinhoff, G, Drey, F, Lepperhof, V, Neef, K, Fatima, A, Wittwer, T, Wahlers, T, Saric, T, Choi, Yh, Fehrenbach, D, Lehner, A, Herrmann, F, Hollweck, T, Pfeifer, S, Wintermantel, E, Kozlik Feldmann, R, Hagl, C, Akra, B, Gyöngyösi, M, Zimmermann, M, Pavo, N, Mildner, M, Lichtenauer, M, Maurer, G, Ankersmit, J, Hacker, S, Mittermayr, R, Haider, T, Nickl, S, Beer, L, Lebherz Eichinger, D, Schweiger, T, Mitterbauer, A, Keibl, C, Werba, G, Frey, M, Ankersmit, Hj, Herrmann, S, Lux, Ca, Holfeld, J, Tepeköylü, C, Wang, Fs, Kozaryn, R, Schaden, W, Grimm, M, Wang, Cj, Urbschat, A, Zacharowski, K, Paulus, P, Avaca, Mj, Kempf, H, Malan, D, Sasse, P, Fleischmann, B, Palecek, J, Dräger, G, Kirschning, A, Zweigerdt, R, Martin, U, Katsirntaki, K, Haller, R, Ulrich, S, Sgodda, M, Puppe, V, Duerr, J, Schmiedl, A, Ochs, M, Cantz, T, Mall, M, Mauritz, C, Lara, Ar, Dahlmann, J, Schwanke, K, Hegermann, J, Skvorc, D, Gawol, A, Azizian, A, Wagner, S, Krause, A, Klopsch, C, Gaebel, R, Kaminski, A, Chichkov, B, Jockenhoevel, S, Klose, K, Roy, R, Kang, Ks, Bieback, K, Nasseri, B, Polchynska, O, Kruttwig, K, Brüggemann, C, Xu, G, Baumgartner, A, Hasun, M, Podesser, Bk, Ludwig, M, Tölk, A, Noack, T, Margaryan, R, Assanta, N, Menciassi, Arianna, Burchielli, S, Matteucci, Marco, Lionetti, Vincenzo, Luchi, C, Cariati, E, Coceani, F, Murzi, B, Rojas, Sv, Rotärmel, A, Nasseri, Ba, Ebell, W, Dandel, M, Kukucka, M, Gebker, R, Mutlak, H, Ockelmann, P, Tacke, S, Scheller, B, Pereszlenyi, A, Meier, M, Schecker, N, Rathert, C, Becher, Pm, Drori Carmi, N, Bercovich, N, Zahavi Goldstein, E, Jack, M, Netzer, N, Pinzur, L, Chajut, A, Tschöpe, C, Ruch, U, Strauer, Be, Tiedemann, G, Schlegel, F, Dhein, S, Akhavuz, O, Mohr, Fw, Dohmen, Pm, Salameh, A, Oelmann, K, Kiefer, P, Merkert, S, Templin, C, Jara Avaca, M, Müller, S, von Haehling, S, Slavic, S, Curato, C, Altarche Xifro, W, Unger, T, Li, J, Zhang, Y, Li, Wz, Ou, L, Ma, N, Haase, A, Alt, R, and Martin, U.
- Published
- 2013
9. TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine.
- Author
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Pascual-Reguant, A, Bayat Sarmadi, J, Baumann, C, Noster, R, Cirera-Salinas, D, Curato, C, Pelczar, P, Huber, S, Zielinski, C E, Löhning, M, Hauser, A E, and Esplugues, E
- Published
- 2017
- Full Text
- View/download PDF
10. 918 - Nanotechnology-based immunotherapeutic approach for tumour eradication
- Author
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Zupančič, E., Curato, C., Eisenbach, L., Jung, S., and Florindo, H.
- Published
- 2016
- Full Text
- View/download PDF
11. 3rd EACTS Meeting on Cardiac and Pulmonary Regeneration Berlin-Brandenburgische Akademie, Berlin, Germany, 14-15 December 2012
- Author
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Bader, A., primary, Brodarac, A., additional, Hetzer, R., additional, Kurtz, A., additional, Stamm, C., additional, Baraki, H., additional, Kensah, G., additional, Asch, S., additional, Rojas, S., additional, Martens, A., additional, Gruh, I., additional, Haverich, A., additional, Kutschka, I., additional, Cortes-Dericks, L., additional, Froment, L., additional, Kocher, G., additional, Schmid, R. A., additional, Delyagina, E., additional, Schade, A., additional, Scharfenberg, D., additional, Skorska, A., additional, Lux, C., additional, Li, W., additional, Steinhoff, G., additional, Drey, F., additional, Lepperhof, V., additional, Neef, K., additional, Fatima, A., additional, Wittwer, T., additional, Wahlers, T., additional, Saric, T., additional, Choi, Y.- H., additional, Fehrenbach, D., additional, Lehner, A., additional, Herrmann, F., additional, Hollweck, T., additional, Pfeifer, S., additional, Wintermantel, E., additional, Kozlik-Feldmann, R., additional, Hagl, C., additional, Akra, B., additional, Gyongyosi, M., additional, Zimmermann, M., additional, Pavo, N., additional, Mildner, M., additional, Lichtenauer, M., additional, Maurer, G., additional, Ankersmit, J., additional, Hacker, S., additional, Mittermayr, R., additional, Haider, T., additional, Nickl, S., additional, Beer, L., additional, Lebherz-Eichinger, D., additional, Schweiger, T., additional, Mitterbauer, A., additional, Keibl, C., additional, Werba, G., additional, Frey, M., additional, Ankersmit, H. J., additional, Herrmann, S., additional, Lux, C. A., additional, Holfeld, J., additional, Tepekoylu, C., additional, Wang, F.- S., additional, Kozaryn, R., additional, Schaden, W., additional, Grimm, M., additional, Wang, C.- J., additional, Urbschat, A., additional, Zacharowski, K., additional, Paulus, P., additional, Avaca, M. J., additional, Kempf, H., additional, Malan, D., additional, Sasse, P., additional, Fleischmann, B., additional, Palecek, J., additional, Drager, G., additional, Kirschning, A., additional, Zweigerdt, R., additional, Martin, U., additional, Katsirntaki, K., additional, Haller, R., additional, Ulrich, S., additional, Sgodda, M., additional, Puppe, V., additional, Duerr, J., additional, Schmiedl, A., additional, Ochs, M., additional, Cantz, T., additional, Mall, M., additional, Mauritz, C., additional, Lara, A. R., additional, Dahlmann, J., additional, Schwanke, K., additional, Hegermann, J., additional, Skvorc, D., additional, Gawol, A., additional, Azizian, A., additional, Wagner, S., additional, Krause, A., additional, Klopsch, C., additional, Gaebel, R., additional, Kaminski, A., additional, Chichkov, B., additional, Jockenhoevel, S., additional, Klose, K., additional, Roy, R., additional, Kang, K.- S., additional, Bieback, K., additional, Nasseri, B., additional, Polchynska, O., additional, Kruttwig, K., additional, Bruggemann, C., additional, Xu, G., additional, Baumgartner, A., additional, Hasun, M., additional, Podesser, B. K., additional, Ludwig, M., additional, Tolk, A., additional, Noack, T., additional, Margaryan, R., additional, Assanta, N., additional, Menciassi, A., additional, Burchielli, S., additional, Matteucci, M., additional, Lionetti, V., additional, Luchi, C., additional, Cariati, E., additional, Coceani, F., additional, Murzi, B., additional, Rojas, S. V., additional, Rotarmel, A., additional, Nasseri, B. A., additional, Ebell, W., additional, Dandel, M., additional, Kukucka, M., additional, Gebker, R., additional, Mutlak, H., additional, Ockelmann, P., additional, Tacke, S., additional, Scheller, B., additional, Pereszlenyi, A., additional, Meier, M., additional, Schecker, N., additional, Rathert, C., additional, Becher, P. M., additional, Drori-Carmi, N., additional, Bercovich, N., additional, Zahavi-Goldstein, E., additional, Jack, M., additional, Netzer, N., additional, Pinzur, L., additional, Chajut, A., additional, Tschope, C., additional, Ruch, U., additional, Strauer, B.- E., additional, Tiedemann, G., additional, Schlegel, F., additional, Dhein, S., additional, Akhavuz, O., additional, Mohr, F. W., additional, Dohmen, P. M., additional, Salameh, A., additional, Oelmann, K., additional, Kiefer, P., additional, Merkert, S., additional, Templin, C., additional, Jara-Avaca, M., additional, Muller, S., additional, von Haehling, S., additional, Slavic, S., additional, Curato, C., additional, Altarche-Xifro, W., additional, Unger, T., additional, Li, J., additional, Zhang, Y., additional, Li, W. Z., additional, Ou, L., additional, Ma, N., additional, Haase, A., additional, and Alt, R., additional
- Published
- 2013
- Full Text
- View/download PDF
12. Angiotensin II Type 2 Receptor Stimulation: A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction?
- Author
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Kaschina E, Grzesiak A, Li J, Foryst-Ludwig A, Timm M, Rompe F, Sommerfeld M, Kemnitz UR, Curato C, Namsolleck P, Tschöpe C, Hallberg A, Alterman M, Hucko T, Paetsch I, Dietrich T, Schnackenburg B, Graf K, Dahlöf B, and Kintscher U
- Published
- 2008
13. Unique and common TCR repertoire features of Ni 2+ -, Co 2+ -, and Pd 2+ -specific human CD154 + CD4+ T cells.
- Author
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Riedel F, Aparicio-Soto M, Curato C, Münch L, Abbas A, Thierse HJ, Peitsch WK, Luch A, and Siewert K
- Subjects
- Humans, Leukocytes, Mononuclear metabolism, Histidine metabolism, Complementarity Determining Regions genetics, Complementarity Determining Regions metabolism, CD4-Positive T-Lymphocytes, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta metabolism
- Abstract
Background: Apart from Ni
2+ , Co2+ , and Pd2+ ions commonly trigger T cell-mediated allergic contact dermatitis. However, in vitro frequencies of metal-specific T cells and the mechanisms of antigen recognition remain unclear., Methods: Here, we utilized a CD154 upregulation assay to quantify Ni2+ -, Co2+ -, and Pd2+ -specific CD4+ T cells in peripheral blood mononuclear cells (PBMC). Involved αβ T cell receptor (TCR) repertoires were analyzed by high-throughput sequencing., Results: Peripheral blood mononuclear cells incubation with NiSO4 , CoCl2 , and PdCl2 increased frequencies of CD154 + CD4+ memory T cells that peaked at ~400 μM. Activation was TCR-mediated as shown by the metal-specific restimulation of T cell clones. Most abundant were Pd2+ -specific T cells (mean 3.5%, n = 19), followed by Co2+ - and Ni2+ -specific cells (0.6%, n = 18 and 0.3%, n = 20) in both allergic and non-allergic individuals. A strong overrepresentation of the gene segment TRAV9-2 was unique for Ni2+ -specific TCR (28% of TCR) while Co2+ and Pd2+ -specific TCR favorably expressed TRAV2 (8%) and the TRBV4 gene segment family (21%), respectively. As a second, independent mechanism of metal ion recognition, all analyzed metal-specific TCR showed a common overrepresentation of a histidine in the complementarity determining region 3 (CDR3; 15% of α-chains, 34% of β-chains). The positions of the CDR3 histidine among metal-specific TCR mirrored those in random repertoires and were conserved among cross-reactive clonotypes., Conclusions: Induced CD154 expression allows a fast and comprehensive detection of Ni2+ -, Co2+ -, and Pd2+ -specific CD4+ T cells. Distinct TCR repertoire features underlie the frequent activation and cross-reactivity of human metal-specific T cells., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)- Published
- 2023
- Full Text
- View/download PDF
14. Interfacial Water in the SARS Spike Protein: Investigating the Interaction with Human ACE2 Receptor and In Vitro Uptake in A549 Cells.
- Author
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Singh AV, Kayal A, Malik A, Maharjan RS, Dietrich P, Thissen A, Siewert K, Curato C, Pande K, Prahlad D, Kulkarni N, Laux P, and Luch A
- Subjects
- A549 Cells, Humans, Molecular Dynamics Simulation, Pandemics, Peptidyl-Dipeptidase A metabolism, Protein Binding, SARS-CoV-2 metabolism, Angiotensin-Converting Enzyme 2 chemistry, Angiotensin-Converting Enzyme 2 metabolism, COVID-19 metabolism, COVID-19 virology, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus metabolism, Water chemistry
- Abstract
The severity of global pandemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has engaged the researchers and clinicians to find the key features triggering the viral infection to lung cells. By utilizing such crucial information, researchers and scientists try to combat the spread of the virus. Here, in this work, we performed in silico analysis of the protein-protein interactions between the receptor-binding domain (RBD) of the viral spike protein and the human angiotensin-converting enzyme 2 (hACE2) receptor to highlight the key alteration that happened from SARS-CoV to SARS-CoV-2. We analyzed and compared the molecular differences between spike proteins of the two viruses using various computational approaches such as binding affinity calculations, computational alanine, and molecular dynamics simulations. The binding affinity calculations showed that SARS-CoV-2 binds a little more firmly to the hACE2 receptor than SARS-CoV. The major finding obtained from molecular dynamics simulations was that the RBD-ACE2 interface is populated with water molecules and interacts strongly with both RBD and ACE2 interfacial residues during the simulation periods. The water-mediated hydrogen bond by the bridge water molecules is crucial for stabilizing the RBD and ACE2 domains. Near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS) confirmed the presence of vapor and molecular water phases in the protein-protein interfacial domain, further validating the computationally predicted interfacial water molecules. In addition, we examined the role of interfacial water molecules in virus uptake by lung cell A549 by binding and maintaining the RBD/hACE2 complex at varying temperatures using nanourchins coated with spike proteins as pseudoviruses and fluorescence-activated cell sorting (FACS) as a quantitative approach. The structural and dynamical features presented here may serve as a guide for developing new drug molecules, vaccines, or antibodies to combat the COVID-19 pandemic.
- Published
- 2022
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15. Frequencies and TCR Repertoires of Human 2,4,6-Trinitrobenzenesulfonic Acid-specific T Cells.
- Author
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Curato C, Aparicio-Soto M, Riedel F, Wehl I, Basaran A, Abbas A, Thierse HJ, Luch A, and Siewert K
- Abstract
Allergic contact dermatitis is a widespread T cell-mediated inflammatory skin disease, but in vitro monitoring of chemical-specific T cells remains challenging. We here introduce short-term CD154/CD137 upregulation to monitor human T cell responses to the experimental sensitizer 2,4,6-trinitrobenzenesulfonic acid (TNBS). Peripheral blood mononuclear cells (PBMC) from healthy donor buffy coats were TNBS-modified and incubated with unmodified PBMC. After 5 and 16 h, we detected TNBS-specific activated CD154+CD4+ and CD137+CD8+ T cells by multi-parameter flow cytometry, respectively. Activated cells were sorted for restimulation and bulk T cell receptor (TCR) high-throughput sequencing (HTS). Stimulation with TNBS-modified cells (3 mM) induced CD154 expression on 0.04% of CD4+ and CD137 expression on 0.60% of CD8+ memory T cells, respectively (means, n = 11-17 donors). CD69 co-expression argued for TCR-mediated activation, which was further supported by TNBS-specific restimulation of 10/13 CD154+CD4+ and 11/15 CD137+CD8+ T cell clones and lines. Major histocompatibility complex (MHC) blocking antibodies prevented activation, illustrating MHC restriction. The high frequencies of TNBS-specific T cells were associated with distinct common changes in the TCR β-chain repertoire. We observed an overrepresentation of tryptophan and lysine in the complementarity determining regions 3 (CDR3) ( n = 3-5 donors), indicating a preferential interaction of these amino acids with the TNBS-induced epitopes. In summary, the detection of TNBS-specific T cells by CD154/CD137 upregulation is a fast, comprehensive and quantitative method. Combined with TCR HTS, the mechanisms of chemical allergen recognition that underlie unusually frequent T cell activation can be assessed. In the future, this approach may be adapted to detect T cells activated by additional chemical sensitizers., 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 Curato, Aparicio-Soto, Riedel, Wehl, Basaran, Abbas, Thierse, Luch and Siewert.)
- Published
- 2022
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16. In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals-A Systematic Review.
- Author
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Aparicio-Soto M, Curato C, Riedel F, Thierse HJ, Luch A, and Siewert K
- Subjects
- Antigens immunology, Epitopes, T-Lymphocyte immunology, Humans, Lymphocyte Activation immunology, Receptors, Antigen, T-Cell metabolism, Allergens immunology, Skin immunology, T-Lymphocytes immunology
- Abstract
Background: Chemical allergies are T cell-mediated diseases that often manifest in the skin as allergic contact dermatitis (ACD). To prevent ACD on a public health scale and avoid elicitation reactions at the individual patient level, predictive and diagnostic tests, respectively, are indispensable. Currently, there is no validated in vitro T cell assay available. The main bottlenecks concern the inefficient generation of T cell epitopes and the detection of rare antigen-specific T cells., Methods: Here, we systematically review original experimental research papers describing T cell activation to chemical skin sensitizers. We focus our search on studies published in the PubMed and Scopus databases on non-metallic allergens in the last 20 years., Results: We identified 37 papers, among them 32 (86%) describing antigen-specific human T cell activation to 31 different chemical allergens. The remaining studies measured the general effects of chemical allergens on T cell function (five studies, 14%). Most antigen-specific studies used peripheral blood mononuclear cells (PBMC) as antigen-presenting cells (APC, 75%) and interrogated the blood T cell pool (91%). Depending on the individual chemical properties, T cell epitopes were generated either by direct administration into the culture medium (72%), separate modification of autologous APC (29%) or by use of hapten-modified model proteins (13%). Read-outs were mainly based on proliferation (91%), often combined with cytokine secretion (53%). The analysis of T cell clones offers additional opportunities to elucidate the mechanisms of epitope formation and cross-reactivity (13%). The best researched allergen was p -phenylenediamine (PPD, 12 studies, 38%). For this and some other allergens, stronger immune responses were observed in some allergic patients (15/31 chemicals, 48%), illustrating the in vivo relevance of the identified T cells while detection limits remain challenging in many cases., Interpretation: Our results illustrate current hardships and possible solutions to monitoring T cell responses to individual chemical skin sensitizers. The provided data can guide the further development of T cell assays to unfold their full predictive and diagnostic potential, including cross-reactivity assessments.
- Published
- 2021
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17. Immunological Mechanisms of Metal Allergies and the Nickel-Specific TCR-pMHC Interface.
- Author
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Riedel F, Aparicio-Soto M, Curato C, Thierse HJ, Siewert K, and Luch A
- Subjects
- Humans, Major Histocompatibility Complex, Peptides, Receptors, Antigen, T-Cell genetics, T-Lymphocytes, Hypersensitivity, Nickel toxicity
- Abstract
Besides having physiological functions and general toxic effects, many metal ions can cause allergic reactions in humans. We here review the immune events involved in the mediation of metal allergies. We focus on nickel (Ni), cobalt (Co) and palladium (Pd), because these allergens are among the most prevalent sensitizers (Ni, Co) and immediate neighbors in the periodic table of the chemical elements. Co-sensitization between Ni and the other two metals is frequent while the knowledge on a possible immunological cross-reactivity using in vivo and in vitro approaches remains limited. At the center of an allergic reaction lies the capability of a metal allergen to form T cell epitopes that are recognized by specific T cell receptors (TCR). Technological advances such as activation-induced marker assays and TCR high-throughput sequencing recently provided new insights into the interaction of Ni
2+ with the αβ TCR-peptide-major histocompatibility complex (pMHC) interface. Ni2+ functionally binds to the TCR gene segment TRAV9-2 or a histidine in the complementarity determining region 3 (CDR3), the main antigen binding region. Thus, we overview known, newly identified and hypothesized mechanisms of metal-specific T cell activation and discuss current knowledge on cross-reactivity.- Published
- 2021
- Full Text
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18. Polyglutamine-Related Aggregates Can Serve as a Potent Antigen Source for Cross-Presentation by Dendritic Cells.
- Author
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Tabachnick-Cherny S, Pinto S, Berko D, Curato C, Wolf Y, Porat Z, Karmona R, Tirosh B, Jung S, and Navon A
- Subjects
- Animals, Antigens genetics, Cell Line, Dendritic Cells metabolism, Epitopes immunology, Female, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class I metabolism, Mice, Mice, Transgenic, Ovalbumin genetics, Ovalbumin immunology, Peptides metabolism, Antigen Presentation, Antigens immunology, Dendritic Cells immunology, Peptides immunology, Protein Aggregates immunology
- Abstract
Protective MHC class I-dependent immune responses require an overlap between repertoires of proteins directly presented on target cells and cross-presented by professional APC, specifically dendritic cells. How stable proteins that rely on defective ribosomal proteins for direct presentation are captured for cell-to-cell transfer remains enigmatic. In this study, we address this issue using a combination of in vitro (C57BL/6-derived mouse cell lines) and in vivo (C57BL/6 mouse strains) approaches involving stable and unstable versions of OVA model Ags displaying defective ribosomal protein-dependent and -independent Ag presentation, respectively. Apoptosis, but not necrosis, of donor cells was found associated with robust global protein aggregate formation and captured stable proteins permissive for cross-presentation. Potency of aggregates to serve as Ag source was directly demonstrated using polyglutamine-equipped model substrates. Collectively, our data implicate global protein aggregation in apoptotic cells as a mechanism that ensures the overlap between MHC class I epitopes presented directly or cross-presented by APC and demonstrate the unusual ability of dendritic cells to process stable protein aggregates., (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Published
- 2020
- Full Text
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19. Intravital visualization of interactions of murine Peyer's patch-resident dendritic cells with M cells.
- Author
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Kolesnikov M, Curato C, Zupancic E, Florindo H, Shakhar G, and Jung S
- Subjects
- Animals, Intravital Microscopy, Lymphocyte Activation, Mice, Mice, Transgenic, Phagocytosis, Transcription Factors genetics, Dendritic Cells immunology, Epithelial Cells immunology, Intestinal Mucosa immunology, Intestine, Small immunology, Peyer's Patches immunology, T-Lymphocytes immunology, Transcription Factors metabolism
- Abstract
The small intestine hosts specialized lymphoid structures, the Peyer's patches, that face the gut lumen and are overlaid with unique epithelial cells, called microfold (M) cells. M cells are considered to constitute an important route for antigen uptake in the mucosal immune system. Here, we used intravital microscopy to define immune cell populations, which are in close contact with M cells and potentially sample antigen. We present live evidence that DCs enter M cell pockets and highlight the abundance of mononuclear phagocytes in these structures. Taking advantage of the respective reporter animals, we focused on classical DCs that express Zbtb46 and analyzed how these cells interact with M cells in steady state and sample antigen for T cell activation in the Peyer's patches following challenge., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2020
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20. Defining murine monocyte differentiation into colonic and ileal macrophages.
- Author
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Gross-Vered M, Trzebanski S, Shemer A, Bernshtein B, Curato C, Stelzer G, Salame TM, David E, Boura-Halfon S, Chappell-Maor L, Leshkowitz D, and Jung S
- Subjects
- Animals, Mice, Specific Pathogen-Free Organisms, Cell Differentiation, Colon physiology, Ileum physiology, Macrophages metabolism, Monocytes cytology
- Abstract
Monocytes are circulating short-lived macrophage precursors that are recruited on demand from the blood to sites of inflammation and challenge. In steady state, classical monocytes give rise to vasculature-resident cells that patrol the luminal side of the endothelium. In addition, classical monocytes feed macrophage compartments of selected organs, including barrier tissues, such as the skin and intestine, as well as the heart. Monocyte differentiation under conditions of inflammation has been studied in considerable detail. In contrast, monocyte differentiation under non-inflammatory conditions remains less well understood. Here we took advantage of a combination of cell ablation and precursor engraftment to investigate the generation of gut macrophages from monocytes. Collectively, we identify factors associated with the gradual adaptation of monocytes to tissue residency. Moreover, comparison of monocyte differentiation into the colon and ileum-resident macrophages revealed the graduated acquisition of gut segment-specific gene expression signatures., Competing Interests: MG, ST, AS, BB, CC, GS, TS, ED, SB, LC, DL, SJ No competing interests declared, (© 2020, Gross-Vered et al.)
- Published
- 2020
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21. IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response.
- Author
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Bernshtein B, Curato C, Ioannou M, Thaiss CA, Gross-Vered M, Kolesnikov M, Wang Q, David E, Chappell-Maor L, Harmelin A, Elinav E, Thakker P, Papayannopoulos V, and Jung S
- Subjects
- Animals, Colitis pathology, Intestines immunology, Intestines pathology, Male, Mice, Neutrophils immunology, Receptors, Interleukin-10 genetics, Interleukin-22, Colitis immunology, Epithelial Cells immunology, Interleukin-23 immunology, Interleukins immunology, Macrophages immunology, Receptors, Interleukin-10 immunology
- Abstract
Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency ( Cx3cr1
Cre :Il10rafl/fl mice), proinflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition observed in children carrying IL-10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that Cx3cr1Cre :Il10rafl/fl :Il23afl/fl mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to proinflammatory macrophages, we provide evidence that T cells of colitic animals produce IL-22, which induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, we define macrophage-specific contributions to the induction and pathogenesis of colitis, as manifested in mice harboring IL-10R deficiencies and human IBDs., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
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22. DC Respond to Cognate T Cell Interaction in the Antigen-Challenged Lymph Node.
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Curato C, Bernshtein B, Zupancič E, Dufner A, Jaitin D, Giladi A, David E, Chappell-Maor L, Leshkowitz D, Knobeloch KP, Amit I, Florindo HF, and Jung S
- Subjects
- Adjuvants, Immunologic administration & dosage, Animals, Antigen Presentation immunology, Antigens, Cytokines immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Cell Communication immunology, Dendritic Cells immunology, Lymph Nodes immunology, Th1 Cells immunology
- Abstract
Dendritic cells (DC) are unrivaled in their potential to prime naive T cells by presenting antigen and providing costimulation. DC are furthermore believed to decode antigen context by virtue of pattern recognition receptors and to polarize T cells through cytokine secretion toward distinct effector functions. Diverse polarized T helper (T
H ) cells have been explored in great detail. In contrast, studies of instructing DC have to date largely been restricted to in vitro settings or adoptively transferred DC. Here we report efforts to unravel the DC response to cognate T cell encounter in antigen-challenged lymph nodes (LN). Mice engrafted with antigen-specific T cells were immunized with nanoparticles (NP) entrapping adjuvants and absorbed with antigen to study the immediate DC response to T cell encounter using bulk and single cell RNA-seq profiling. NP induced robust antigen-specific TH 1 cell responses with minimal bystander activation. Fluorescent-labeled NP allowed identification of antigen-carrying DC and focus on transcriptional changes in DC that encounter T cells. Our results support the existence of a bi-directional crosstalk between DC and T cells that promotes TH 1 responses, including involvement of the ubiquitin-like molecule Isg15 that merits further study.- Published
- 2019
- Full Text
- View/download PDF
23. Nanoparticulate vaccine inhibits tumor growth via improved T cell recruitment into melanoma and huHER2 breast cancer.
- Author
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Zupančič E, Curato C, Kim JS, Yeini E, Porat Z, Viana AS, Globerson-Levin A, Waks T, Eshhar Z, Moreira JN, Satchi-Fainaro R, Eisenbach L, Jung S, and Florindo HF
- Subjects
- Animals, Breast Neoplasms immunology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cancer Vaccines chemistry, Carcinogenesis metabolism, Carcinogenesis pathology, Female, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Nanoparticles chemistry, Tumor Cells, Cultured, Breast Neoplasms prevention & control, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines administration & dosage, Carcinogenesis drug effects, Nanoparticles administration & dosage, T-Lymphocytes, Cytotoxic immunology
- Abstract
Nanoparticulate vaccines are promising tools to overcome cancer immune evasion. However, a deeper understanding on nanoparticle-immune cell interactions and treatments regime is required for optimal efficacy. We provide a comprehensive study of treatment schedules and mode of antigen-association to nanovaccines on the modulation of T cell immunity in vivo, under steady-state and tumor-bearing mice. The coordinated delivery of antigen and two adjuvants (Monophosphoryl lipid A, oligodeoxynucleotide cytosine-phosphate-guanine motifs (CpG)) by nanoparticles was crucial for dendritic cell activation. A single vaccination dictated a 3-fold increase on cytotoxic memory-T cells and raised antigen-specific immune responses against B16.M05 melanoma. It generated at least a 5-fold increase on IFN-γ cytokine production, and presented over 50% higher lymphocyte count in the tumor microenvironment, compared to the control. The number of lymphocytes at the tumor site doubled with triple immunization. This lymphocyte infiltration pattern was confirmed in mammary huHER2 carcinoma, with significant tumor reduction., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
24. ICAMs Are Not Obligatory for Functional Immune Synapses between Naive CD4 T Cells and Lymph Node DCs.
- Author
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Feigelson SW, Solomon A, Biram A, Hatzav M, Lichtenstein M, Regev O, Kozlovski S, Varol D, Curato C, Leshkowitz D, Jung S, Shulman Z, and Alon R
- Subjects
- Humans, CD4-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Intercellular Adhesion Molecule-1 genetics, Lymph Nodes immunology
- Abstract
Protective immune responses depend on the formation of immune synapses between T cells and antigen-presenting cells (APCs). The two main LFA-1 ligands, ICAM-1 and ICAM-2, are co-expressed on many cell types, including APCs and blood vessels. Although these molecules were suggested to be key players in immune synapses studied in vitro, their contribution to helper T cell priming in vivo is unclear. Here, we used transgenic mice and intravital imaging to examine the role of dendritic cell (DC) ICAM-1 and ICAM-2 in naive CD4 T cell priming and differentiation in skin-draining lymph nodes. Surprisingly, ICAM deficiency on endogenous CD40-stimulated lymph node DCs did not impair their ability to arrest and prime CD4 lymphocyte activation and differentiation into Th1 and Tfh effectors. Thus, functional T cell receptor (TCR)-specific helper T cell synapses with antigen-presenting DCs and subsequent proliferation and early differentiation into T effectors do not require LFA-1-mediated T cell adhesiveness to DC ICAMs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
25. Rac1 functions downstream of miR-142 in regulation of erythropoiesis.
- Author
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Rivkin N, Chapnik E, Birger Y, Yanowski E, Curato C, Mildner A, Porat Z, Amir G, Izraeli S, Jung S, and Hornstein E
- Subjects
- Animals, Cell Differentiation, Cell Proliferation, Humans, Erythropoiesis, MicroRNAs physiology, rac1 GTP-Binding Protein physiology
- Published
- 2017
- Full Text
- View/download PDF
26. T H 17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine.
- Author
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Pascual-Reguant A, Bayat Sarmadi J, Baumann C, Noster R, Cirera-Salinas D, Curato C, Pelczar P, Huber S, Zielinski CE, Löhning M, Hauser AE, and Esplugues E
- Subjects
- Animals, Cells, Cultured, Homeostasis, Interleukin-1 Receptor-Like 1 Protein genetics, Interleukin-10 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, Alarmins metabolism, Inflammation immunology, Interleukin-1 Receptor-Like 1 Protein metabolism, Interleukin-33 metabolism, Intestine, Small immunology, T-Lymphocytes, Regulatory immunology, Th17 Cells immunology
- Abstract
T
H 17 cells are major drivers of inflammation and involved in several autoimmune diseases. Tissue inflammation is a beneficial host response to infection, but it can also contribute to autoimmunity. The crosstalk between a tissue and the immune system during an inflammatory response is key for preserving tissue integrity and restoring physiological processes. However, how the inflamed tissue regulates the magnitude of an immune response by controlling pro-inflammatory T cells is not well characterized so far. Here we show that TH 17 cells accumulating in the small intestine upon inflammation express the IL-33 receptor (ST2) and intestinal epithelial cells (IEC) are the main source of the alarmin interleukin-33 (IL-33). We show that pro-inflammatory TH 17 cells acquire a regulatory phenotype with immunosuppressive properties in response to IL-33. Absence of ST2 signaling promotes the secretion of pro-inflammatory cytokines by TH 17 cells and dampens the secretion of IL-10. Our results provide new insights into the mechanisms by which IEC, via IL-33/ST2 axis, may control pro-inflammatory TH 17 cells in the small intestine to sustain homeostasis.- Published
- 2017
- Full Text
- View/download PDF
27. Rational design of nanoparticles towards targeting antigen-presenting cells and improved T cell priming.
- Author
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Zupančič E, Curato C, Paisana M, Rodrigues C, Porat Z, Viana AS, Afonso CAM, Pinto J, Gaspar R, Moreira JN, Satchi-Fainaro R, Jung S, and Florindo HF
- Subjects
- Animals, Antigens immunology, Cytokines immunology, Drug Delivery Systems, Female, Immunization, Lymph Nodes cytology, Lymph Nodes immunology, Lymphocyte Activation, Mice, Inbred C57BL, Nanoparticles ultrastructure, Ovalbumin immunology, Polylactic Acid-Polyglycolic Acid Copolymer, Surface-Active Agents chemistry, Antigens administration & dosage, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Lactic Acid chemistry, Nanoparticles chemistry, Ovalbumin administration & dosage, Polyglycolic Acid chemistry
- Abstract
Vaccination is a promising strategy to trigger and boost immune responses against cancer or infectious disease. We have designed, synthesized and characterized aliphatic-polyester (poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to investigate how the nature of protein association (adsorbed versus entrapped) and polymer/surfactant concentrations impact on the generation and modulation of antigen-specific immune responses. The ability of the NP formulations to target dendritic cells (DC), be internalized and activate the T cells was characterized and optimized in vitro and in vivo using markers of DC activation and co-stimulatory molecules. Ovalbumin (OVA) was used as a model antigen in combination with the engraftment of CD4
+ and CD8+ T cells, carrying a transgenic OVA-responding T cell receptor (TCR), to trace and characterize the activation of antigen-specific CD4+ and CD8+ lymph node T cells upon NP vaccination. Accordingly, the phenotype and frequency of immune cell stimulation induced by the NP loaded with OVA, isolated or in combination with synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotide (ODN) motifs, were characterized. DC-NP interactions increased with incubation time, presenting internalization values between 50 and 60% and 30-40%, in vitro and in vivo, respectively. Interestingly, animal immunization with antigen-adsorbed NP up-regulated major histocompatibility complex (MHC) class II (MHCII), while NP entrapping the antigen up-regulated MHCI, suggesting a more efficient cross-presentation. On the other hand, rather surprisingly, the surfactant used in the NP formulation had a major impact on the activation of antigen presenting cells (APC). In fact, DC collected from lymph nodes of animals immunized with NP prepared using poly(vinil alcohol) (PVA), as a surfactant, expressed significantly higher levels of CD86, MHCI and MHCII. In addition, those NP prepared with PVA and co-entrapping OVA and the toll-like receptor (TLR) ligand CpG, induced the most profound antigen-specific T cell response, by both CD4+ and CD8+ T cells, in vivo. Overall, our data reveal the impact of NP composition and surface properties on the type and extension of induced immune responses. Deeper understanding on the NP-immune cell crosstalk can guide the rational development of nano-immunotherapeutic systems with improved and specific therapeutic efficacy and avoiding off-target effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
28. Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury.
- Author
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Reichetzeder C, von Websky K, Tsuprykov O, Mohagheghi Samarin A, Falke LG, Dwi Putra SE, Hasan AA, Antonenko V, Curato C, Rippmann J, Klein T, and Hocher B
- Subjects
- Adamantane administration & dosage, Adamantane chemistry, Adamantane pharmacology, Animals, Dipeptidyl Peptidase 4 metabolism, Dipeptidyl-Peptidase IV Inhibitors administration & dosage, Dipeptidyl-Peptidase IV Inhibitors chemistry, Dose-Response Relationship, Drug, Kidney metabolism, Kidney pathology, Linagliptin administration & dosage, Linagliptin chemistry, Male, Molecular Structure, Nitriles administration & dosage, Nitriles chemistry, Pyrrolidines administration & dosage, Pyrrolidines chemistry, Rats, Rats, Wistar, Reperfusion Injury metabolism, Reperfusion Injury pathology, Sitagliptin Phosphate administration & dosage, Sitagliptin Phosphate chemistry, Structure-Activity Relationship, Vildagliptin, Adamantane analogs & derivatives, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Kidney drug effects, Linagliptin pharmacology, Nitriles pharmacology, Pyrrolidines pharmacology, Reperfusion Injury drug therapy, Sitagliptin Phosphate pharmacology
- Abstract
Background and Purpose: Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI., Experimental Approach: IRI was induced in uninephrectomized male rats by renal artery clamping for 30 min. The sham group was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p.o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg·kg
-1 ·day-1 ), vildagliptin (8 mg·kg-1 ·day-1 ) and sitagliptin (30 mg·kg-1 ·day-1 ). An additional group received sitagliptin until study end (before IRI: 30 mg·kg-1 ·day-1 ; after IRI: 15 mg·kg-1 ·day-1 )., Key Results: Plasma-active glucagon-like peptide type 1 (GLP-1) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP-1 plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group., Conclusions and Implications: In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage., (© 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2017
- Full Text
- View/download PDF
29. Depletion of Cultivatable Gut Microbiota by Broad-Spectrum Antibiotic Pretreatment Worsens Outcome After Murine Stroke.
- Author
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Winek K, Engel O, Koduah P, Heimesaat MM, Fischer A, Bereswill S, Dames C, Kershaw O, Gruber AD, Curato C, Oyama N, Meisel C, Meisel A, and Dirnagl U
- Subjects
- Animals, Female, Infarction, Middle Cerebral Artery microbiology, Mice, Mice, Inbred C57BL, Anti-Bacterial Agents pharmacology, Gastrointestinal Microbiome drug effects, Stroke microbiology
- Abstract
Background and Purpose: Antibiotics disturbing microbiota are often used in treatment of poststroke infections. A bidirectional brain-gut microbiota axis was recently suggested as a modulator of nervous system diseases. We hypothesized that gut microbiota may be an important player in the course of stroke., Methods: We investigated the outcome of focal cerebral ischemia in C57BL/6J mice after an 8-week decontamination with quintuple broad-spectrum antibiotic cocktail. These microbiota-depleted animals were subjected to 60 minutes middle cerebral artery occlusion or sham operation. Infarct volume was measured using magnetic resonance imaging, and mice were monitored clinically throughout the whole experiment. At the end point, tissues were preserved for further analysis, comprising histology and immunologic investigations using flow cytometry., Results: We found significantly decreased survival in the middle cerebral artery occlusion microbiota-depleted mice when the antibiotic cocktail was stopped 3 days before surgery (compared with middle cerebral artery occlusion specific pathogen-free and sham-operated microbiota-depleted mice). Moreover, all microbiota-depleted animals in which antibiotic treatment was terminated developed severe acute colitis. This phenotype was rescued by continuous antibiotic treatment or colonization with specific pathogen-free microbiota before surgery. Further, infarct volumes on day one did not differ between any of the experimental groups., Conclusions: Conventional microbiota ensures intestinal protection in the mouse model of experimental stroke and prevents development of acute and severe colitis in microbiota-depleted mice not given antibiotic protection after cerebral ischemia. Our experiments raise the clinically important question as to whether microbial colonization or specific microbiota are crucial for stroke outcome., (© 2016 The Authors.)
- Published
- 2016
- Full Text
- View/download PDF
30. In Vivo Analysis of Intestinal Mononuclear Phagocytes.
- Author
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Curato C, Bernshtein B, Aychek T, and Jung S
- Subjects
- Animals, CX3C Chemokine Receptor 1 genetics, CX3C Chemokine Receptor 1 metabolism, Dendritic Cells cytology, Diphtheria Toxin pharmacology, Heparin-binding EGF-like Growth Factor genetics, Heparin-binding EGF-like Growth Factor metabolism, Homeostasis, Intestinal Mucosa metabolism, Mice, Mice, Transgenic, Monocytes cytology, Mutagenesis, Dendritic Cells metabolism, Intestines cytology, Monocytes metabolism
- Abstract
The study of the intestinal dendritic cell (DC) compartment, its homeostasis, regulation, and response to challenges calls for the investigation within the physiological tissue context comprising the unique anatomic constellation of the epithelial single cell layer and the luminal microbiota, as well as neighboring immune and nonimmune cells. Here we provide protocols we developed that use a combination of conditional cell ablation, conditional compartment mutagenesis, and adoptive precursor transfers to study DC and other intestinal mononuclear phagocytes in in vivo context. We will highlight pitfalls and strengths of these approaches.
- Published
- 2016
- Full Text
- View/download PDF
31. The CD4(+) AT2R(+) T cell subpopulation improves post-infarction remodelling and restores cardiac function.
- Author
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Skorska A, von Haehling S, Ludwig M, Lux CA, Gaebel R, Kleiner G, Klopsch C, Dong J, Curato C, Altarche-Xifró W, Slavic S, Unger T, Steinhoff G, Li J, and David R
- Subjects
- Animals, Cardiotonic Agents metabolism, Heart Failure blood, Heart Failure complications, Heart Failure immunology, Heart Failure physiopathology, Humans, Immunomodulation, Interleukin-10 blood, Myocardial Infarction blood, Myocardial Infarction complications, Myocardial Ischemia blood, Myocardial Ischemia complications, Myocardial Ischemia immunology, Myocardial Ischemia physiopathology, Rats, Wistar, Tumor Necrosis Factor-alpha blood, CD4-Positive T-Lymphocytes immunology, Heart Function Tests, Myocardial Infarction immunology, Myocardial Infarction physiopathology, Receptor, Angiotensin, Type 2 metabolism, Ventricular Remodeling
- Abstract
Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4(+) AT2R(+) cells in the rat heart and spleen post-infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4(+) AT2R(+) T cells in circulating blood, post-infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4(+) cells. CD4(+) AT2R(+) T cells within blood CD4(+) T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4(+) AT2R(+) T cells which expressed regulatory FoxP3, secreted interleukin-10 and other inflammatory-related cytokines. Furthermore, intramyocardial injection of MI-induced splenic CD4(+) AT2R(+) T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4(+) AT2R(+) cells as a T cell subset improving heart function post-MI corresponding with reduced infarction size in a rat MI-model. Our results indicate CD4(+) AT2R(+) cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Published
- 2015
- Full Text
- View/download PDF
32. Vascular change and opposing effects of the angiotensin type 2 receptor in a mouse model of vascular cognitive impairment.
- Author
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Füchtemeier M, Brinckmann MP, Foddis M, Kunz A, Po C, Curato C, Dirnagl U, and Farr TD
- Subjects
- Angiotensin II Type 2 Receptor Blockers pharmacology, Animals, Brain drug effects, Brain metabolism, Cerebrovascular Circulation drug effects, Dementia, Vascular metabolism, Disease Models, Animal, Flow Cytometry, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Brain pathology, Cerebrovascular Circulation physiology, Dementia, Vascular pathology, Receptor, Angiotensin, Type 2 metabolism
- Abstract
Our aims were to assess the spatiotemporal development of brain pathology in a mouse model of chronic hypoperfusion using magnetic resonance imaging (MRI), and to test whether the renin-angiotensin system (RAS) can offer therapeutic benefit. For the first time, different patterns of cerebral blood flow alterations were observed in hypoperfused mice that ranged from an immediate and dramatic to a delayed decrease in cerebral perfusion. Diffusion tensor imaging revealed increases in several quantitative parameters in different brain regions that are indicative of white-matter degeneration; this began around 3 weeks after induction of hypoperfusion. While this model may be more variable than previously reported, neuroimaging tools represent a promising way to identify surrogate markers of pathology. Vascular remodelling was observed in hypoperfused mice, particularly in the anterior part of the Circle of Willis. While the angiotensin II receptor type 2 agonist, Compound 21 (C21), did not influence this response, it did promote expansion of the basilar artery in microcoil animals. Furthermore, C21-treated animals exhibited increased brain lymphocyte infiltration, and importantly, C21 had opposing effects on spatial reference memory in hypoperfused and sham mice. These results suggest that the RAS may have a role in vascular cognitive impairment.
- Published
- 2015
- Full Text
- View/download PDF
33. Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury.
- Author
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Curato C, Slavic S, Dong J, Skorska A, Altarche-Xifró W, Miteva K, Kaschina E, Thiel A, Imboden H, Wang J, Steckelings U, Steinhoff G, Unger T, and Li J
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Cell Separation methods, Flow Cytometry methods, Fluorescent Antibody Technique, Gene Expression, Interleukin-10 immunology, Male, Myocardial Infarction metabolism, Myocardial Ischemia immunology, Myocardial Ischemia metabolism, Myocardium metabolism, Myocardium pathology, Rats, Rats, Wistar, Receptor, Angiotensin, Type 2 metabolism, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocyte Subsets immunology, CD8-Positive T-Lymphocytes immunology, Interleukin-10 biosynthesis, Myocardial Infarction immunology, Myocardium immunology, Receptor, Angiotensin, Type 2 immunology, T-Lymphocyte Subsets metabolism
- Abstract
Emerging evidence suggests a cardioprotective role of the angiotensin AT2R, albeit the underlying cellular mechanisms are not well understood. We aimed in this article to elucidate a potential role of cardiac angiotensin AT2R in regulating cellular immune response to ischemic heart injury. Seven days after myocardial infarction in rats, double-immunofluorescence staining showed that AT2R was detected in a fraction of CD8(+) T cells infiltrating in the peri-infarct myocardium. We developed a method that allowed the isolation of myocardial infiltrating CD8(+)AT2R(+) T cells using modified MACS, and further characterization and purification with flow cytometry. Although the CD8(+)AT2R(-) T cells exhibited potent cytotoxicity to both adult and fetal cardiomyocytes (CMs), the CD8(+)AT2R(+) T cells were noncytotoxic to these CMs. The CD8(+)AT2R(+) T cells were characterized by upregulated IL-10 and downregulated IL-2 and INF-γ expression when compared with CD8(+)AT2R(-) T cells. We further showed that IL-10 gene expression was enhanced in CD8(+) T cells on in vitro AT2R stimulation. Importantly, in vivo AT2R activation engendered an increment of CD8(+)AT2R(+) T cells and IL-10 production in the ischemic myocardium. In addition, intramyocardial transplantation of CD8(+)AT2R(+) T cells (versus CD8(+)AT2R(-)) led to reduced ischemic heart injury. Moreover, the CD8(+)AT2R(+) T cell population was also demonstrated in human peripheral blood. Thus, we have defined the cardioprotective CD8(+)AT2R(+) T cell population, which increases during ischemic heart injury and contributes to maintaining CM viability and providing IL-10, hence revealing an AT2R-mediated cellular mechanism in modulating adaptive immune response in the heart.
- Published
- 2010
- Full Text
- View/download PDF
34. Identification and characterization of the CD4+AT2R+ T cell subpo-pulation in rats and humans.
- Author
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Skorska A, Curato C, Altarche-Xifró W, Slavic S, Unger T, Steinhoff G, and Li J
- Published
- 2010
35. Cardiac c-kit+AT2+ cell population is increased in response to ischemic injury and supports cardiomyocyte performance.
- Author
-
Altarche-Xifró W, Curato C, Kaschina E, Grzesiak A, Slavic S, Dong J, Kappert K, Steckelings M, Imboden H, Unger T, and Li J
- Subjects
- Angiotensins metabolism, Angiotensins pharmacology, Animals, Cardiotonic Agents metabolism, Cardiotonic Agents pharmacology, Cell Differentiation physiology, Cell Proliferation drug effects, Cells, Cultured, Cytoprotection drug effects, Cytoprotection physiology, Flow Cytometry, Fluorescent Antibody Technique, Male, Myocardial Ischemia physiopathology, Myocytes, Cardiac cytology, Rats, Rats, Wistar, Signal Transduction physiology, Stem Cells cytology, Transcription Factors metabolism, Myocardial Ischemia metabolism, Myocytes, Cardiac metabolism, Proto-Oncogene Proteins c-kit metabolism, Receptor, Angiotensin, Type 2 metabolism, Regeneration physiology, Stem Cells metabolism
- Abstract
The expression pattern of angiotensin AT2 receptors with predominance during fetal life and upregulation under pathological conditions during tissue injury/repair process suggests that AT2 receptors may exert an important action in injury/repair adaptive mechanisms. Less is known about AT2 receptors in acute ischemia-induced cardiac injury. We aimed here to elucidate the role of AT2 receptors after acute myocardial infarction. Double immunofluorescence staining showed that cardiac AT2 receptors were mainly detected in clusters of small c-kit+ cells accumulating in peri-infarct zone and c-kit+AT2+ cells increased in response to acute cardiac injury. Further, we isolated cardiac c-kit+AT2+ cell population by modified magnetic activated cell sorting and fluorescence activated cell sorting. These cardiac c-kit+AT2+ cells, represented approximately 0.19% of total cardiac cells in infarcted heart, were characterized by upregulated transcription factors implicated in cardiogenic differentiation (Gata-4, Notch-2, Nkx-2.5) and genes required for self-renewal (Tbx-3, c-Myc, Akt). When adult cardiomyocytes and cardiac c-kit+AT2+ cells isolated from infarcted rat hearts were cocultured, AT2 receptor stimulation in vitro inhibited apoptosis of these cocultured cardiomyocytes. Moreover, in vivo AT2 receptor stimulation led to an increased c-kit+AT2+ cell population in the infarcted myocardium and reduced apoptosis of cardiomyocytes in rats with acute myocardial infarction. These data suggest that cardiac c-kit+AT2+ cell population exists and increases after acute ischemic injury. AT2 receptor activation supports performance of cardiomyocytes, thus contributing to cardioprotection via cardiac c-kit+AT2+ cell population.
- Published
- 2009
- Full Text
- View/download PDF
36. Estrogen receptor alpha supports cardiomyocytes indirectly through post-infarct cardiac c-kit+ cells.
- Author
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Brinckmann M, Kaschina E, Altarche-Xifró W, Curato C, Timm M, Grzesiak A, Dong J, Kappert K, Kintscher U, Unger T, and Li J
- Subjects
- Animals, Cell Differentiation drug effects, Cell Line, Cell Proliferation drug effects, Coculture Techniques, Estradiol pharmacology, Estrogen Receptor alpha agonists, Estrogen Receptor alpha metabolism, Flow Cytometry, Fluorescent Antibody Technique, Immunoblotting, Male, Myoblasts cytology, Myoblasts drug effects, Myoblasts metabolism, Myocytes, Cardiac cytology, Myocytes, Cardiac drug effects, Phenols, Polymerase Chain Reaction, Pyrazoles pharmacology, Rats, Rats, Wistar, Estrogen Receptor alpha physiology, Myocardial Infarction metabolism, Myocytes, Cardiac metabolism, Proto-Oncogene Proteins c-kit metabolism
- Abstract
Despite previous studies demonstrating a cardioprotective role of estradiol via its estrogen receptor (ER)alpha, the underlying mechanisms remain unclear. Here we aimed to define ERalpha-involved mechanisms against cardiac injury. Seven days after myocardial infarction in male rats, cardiac ERalpha was upregulated in post-infarct cardiac c-kit+ cells accumulating in periinfarct myocardium as shown by Western blotting and immunofluorescence staining. Further, we isolated post-infarct cardiac c-kit+ cell population by modified magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS), and confirmed predominant ERalpha expression in this post-infarct cardiac c-kit+ cell population by real-time PCR. These post-infarct cardiac c-kit+ cells, characterized by upregulated transcription factors implicated in cardiogenic differentiation (GATA-4, Notch-2) and genes required for self-renewal (Tbx3, Akt), maintained a stable phenotype in vitro for more than 3 months. ERalpha stimulation supported proliferation but prevented differentiation of undifferentiated myoblast cells. When adult myocytes isolated from infarcted rat hearts were co-cultured with post-infarct cardiac c-kit+ cells, ERalpha stimulation inhibited apoptosis and enhanced survival of these myocytes. These findings suggest that cardiac ERalpha supports survival of cardiomyocytes through post-infarct cardiac c-kit+ cells, which may contribute to cardioprotection against cardiac injury.
- Published
- 2009
- Full Text
- View/download PDF
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