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1. Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome

Author

Gallage, Suchira, Irvine, Elaine E., Barragan Avila, Jose Efren, Reen, Virinder, Pedroni, Silvia M. A., Duran, Imanol, Ranvir, Vikas, Khadayate, Sanjay, Pombo, Joaquim, Brookes, Sharon, Heide, Danijela, Dharmalingham, Gopuraja, Choudhury, Agharul I., Singh, Indrabahadur, Herranz, Nicolás, Vernia, Santiago, Heikenwalder, Mathias, Gil, Jesús, and Withers, Dominic J.

Published
2024
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2. A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1

Author

Gallage, Suchira, Ali, Adnan, Barragan Avila, Jose Efren, Seymen, Nogayhan, Ramadori, Pierluigi, Joerke, Vera, Zizmare, Laimdota, Aicher, David, Gopalsamy, Indresh K., Fong, Winnie, Kosla, Jan, Focaccia, Enrico, Li, Xin, Yousuf, Suhail, Sijmonsma, Tjeerd, Rahbari, Mohammad, Kommoss, Katharina S., Billeter, Adrian, Prokosch, Sandra, Rothermel, Ulrike, Mueller, Florian, Hetzer, Jenny, Heide, Danijela, Schinkel, Benjamin, Machauer, Tim, Pichler, Bernd, Malek, Nisar P., Longerich, Thomas, Roth, Susanne, Rose, Adam J., Schwenck, Johannes, Trautwein, Christoph, Karimi, Mohammad M., and Heikenwalder, Mathias

Published
2024
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3. Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF.

Author

Hausmann, Annika, Felmy, Boas, Kunz, Leo, Kroon, Sanne, Berthold, Dorothée, Ganz, Giverny, Sandu, Ioana, Nakamura, Toshihiro, Zangger, Nathan, Zhang, Yang, Dolowschiak, Tamas, Fattinger, Stefan, Furter, Markus, Müller-Hauser, Anna, Barthel, Manja, Vlantis, Katerina, Wachsmuth, Laurens, Kisielow, Jan, Tortola, Luigi, Heide, Danijela, Heikenwälder, Mathias, Oxenius, Annette, Kopf, Manfred, Schroeder, Timm, Pasparakis, Manolis, Sellin, Mikael, and Hardt, Wolf-Dietrich

Subjects
Animals, Anti-Bacterial Agents, Epithelial Cells, Gene Expression Regulation, Inflammation, Intestinal Mucosa, Intestines, Macrophages, Mice, Mice, Inbred C57BL, NF-kappa B, Signal Transduction, Tumor Necrosis Factors
Abstract

Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.

Published
2021

4. Targeting the liver clock improves fibrosis by restoring TGF-β signaling

Author

Crouchet, Emilie, Dachraoui, Mayssa, Jühling, Frank, Roehlen, Natascha, Oudot, Marine A., Durand, Sarah C., Ponsolles, Clara, Gadenne, Cloé, Meiss-Heydmann, Laura, Moehlin, Julien, Martin, Romain, Brignon, Nicolas, Del Zompo, Fabio, Teraoka, Yuji, Aikata, Hiroshi, Abe-Chayama, Hiromi, Chayama, Kazuaki, Saviano, Antonio, Heide, Danijela, Onea, Mihaela, Geyer, Lucas, Wolf, Thibaut, Felli, Emanuele, Pessaux, Patrick, Heikenwälder, Mathias, Chambon, Pierre, Schuster, Catherine, Lupberger, Joachim, Mukherji, Atish, and Baumert, Thomas F.

Published
2024
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6. Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation

Author

Colasanti, Ombretta, Burm, Rani, Huang, Hao-En, Riedl, Tobias, Traut, Jannik, Gillich, Nadine, Li, Teng-Feng, Corneillie, Laura, Faure-Dupuy, Suzanne, Grünvogel, Oliver, Heide, Danijela, Lee, Ji-Young, Tran, Cong Si, Merle, Uta, Chironna, Maria, Vondran, Florian F.W., Esser-Nobis, Katharina, Binder, Marco, Bartenschlager, Ralf, Heikenwälder, Mathias, Meuleman, Philip, and Lohmann, Volker

Published
2023
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7. OS-103 Antibiotic-mediated microbiota depletion limits IgA-related fibrogenesis in metabolic dysfunction-associated steatohepatitis

Author

Schuehle, Svenja, primary, Kotsiliti, Eleni, additional, Cohen, Yotam, additional, Deng, Sisi, additional, Omer, Hélčne, additional, Han, Feng, additional, Qiu, Mengjie, additional, Zonouzi, Aysan Poursadegh, additional, Schmidt, Sabine, additional, Avila, Jose Efren Barragan, additional, Vaquero, Mirian Fernández, additional, Focaccia, Enrico, additional, Prokosch, Sandra, additional, Rothermel, Ulrike, additional, Müller, Florian, additional, Hetzer, Jenny, additional, Heide, Danijela, additional, Mager, Lukas, additional, Bucci, Daniele, additional, Waisman, Ari, additional, Trautwein, Christoph, additional, Haller, Dirk, additional, Elinav, Eran, additional, and Heikenwälder, Mathias, additional

Published
2024
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8. Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling

Author

Rosenberg, Nofar, Van Haele, Matthias, Lanton, Tali, Brashi, Neta, Bromberg, Zohar, Adler, Hanan, Giladi, Hilla, Peled, Amnon, Goldenberg, Daniel S., Axelrod, Jonathan H., Simerzin, Alina, Chai, Chofit, Paldor, Mor, Markezana, Auerlia, Yaish, Dayana, Shemulian, Zohar, Gross, Dvora, Barnoy, Shanny, Gefen, Maytal, Amran, Osher, Claerhout, Sofie, Fernández-Vaquero, Mirian, García-Beccaria, María, Heide, Danijela, Shoshkes-Carmel, Michal, Schmidt Arras, Dirk, Elgavish, Sharona, Nevo, Yuval, Benyamini, Hadar, Tirnitz-Parker, Janina E.E., Sanchez, Aranzazu, Herrera, Blanca, Safadi, Rifaat, Kaestner, Klaus H., Rose-John, Stefan, Roskams, Tania, Heikenwalder, Mathias, and Galun, Eithan

Published
2022
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9. Lymphotoxin beta‐activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.

Author

Xu, Kaiyu, Kessler, Annika, Nichetti, Federico, Hoffmeister‐Wittmann, Paula, Scherr, Anna‐Lena, Nader, Luisa, Kelmendi, Eblina, Schmitt, Nathalie, Schwab, Maximilian, García‐Beccaria, María, Sobol, Benjamin, Nieto, Osama Azzam, Isele, Hanna, Gärtner, Ulrike, Vaquero‐Siguero, Nuria, Volk, Julia, Korell, Felix, Mock, Andreas, Heide, Danijela, and Ramadori, Pierluigi

Subjects
TRANSCRIPTION factors, GENE expression, SMALL molecules, CELLULAR signal transduction, BILE ducts
Abstract

Background and Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non‐canonical NF‐κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin‐β (LTβ) stimulates the NF‐κB‐inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non‐canonical NF‐κB signalling pathway via the LTβ/NIK/RelB axis in CCA carcinogenesis and progression has not been established. Methods: Human CCA‐derived cell lines and organoids were examined to determine the expression of NF‐κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real‐time impedance measurement and flow cytometry. Immunoblot, qRT‐PCR, RNA sequencing and in situ hybridization were employed to analyse gene and protein expression. Four in vivo models of iCCA were used to probe the activation and regulation of the non‐canonical NF‐κB pathway. Results: Exposure to LTα1/β2 activates the LTβ/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient‐derived CCA organoids and nuclear co‐translocation of RelB and p52 stimulated by LTα1/β2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTβ is the predominant ligand of the non‐canonical NF‐κB signalling pathway. Conclusions: Our study confirms that the non‐canonical NF‐κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target. [ABSTRACT FROM AUTHOR]

Published
2024
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10. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Muller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lennggenhager, Daniela, Moncsek, Anja, and Heide, Danijela

Subjects
Fatty liver -- Complications and side effects, Immunotherapy -- Methods, Patient monitoring -- Methods, Hepatoma -- Care and treatment -- Causes of, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes.sup.1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need.sup.6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8.sup.+PD1.sup.+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8.sup.+PD1.sup.+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8.sup.+PD1.sup.+CXCR6.sup.+, TOX.sup.+, and TNF.sup.+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8.sup.+ T cells or TNF neutralization, suggesting that CD8.sup.+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8.sup.+PD1.sup.+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment. In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy., Author(s): Dominik Pfister [sup.1] [sup.82] , Nicolás Gonzalo Núñez [sup.2] , Roser Pinyol [sup.3] , Olivier Govaere [sup.4] , Matthias Pinter [sup.5] [sup.6] , Marta Szydlowska [sup.1] , Revant Gupta [...]

Published
2021
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11. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Author

Dudek, Michael, Pfister, Dominik, Donakonda, Sainitin, Filpe, Pamela, Schneider, Annika, Laschinger, Melanie, Hartmann, Daniel, Hüser, Norbert, Meiser, Philippa, Bayerl, Felix, Inverso, Donato, Wigger, Jennifer, Sebode, Marcial, Öllinger, Rupert, Rad, Roland, Hegenbarth, Silke, Anton, Martina, Guillot, Adrien, Bowman, Andrew, Heide, Danijela, Müller, Florian, Ramadori, Pierluigi, Leone, Valentina, Garcia-Caceres, Cristina, Gruber, Tim, Seifert, Gabriel, Kabat, Agnieszka M., Mallm, Jan-Philipp, Reider, Simon, Effenberger, Maria, Roth, Susanne, Billeter, Adrian T., Müller-Stich, Beat, Pearce, Edward J., Koch-Nolte, Friedrich, Käser, Rafael, Tilg, Herbert, Thimme, Robert, Boettler, Tobias, Tacke, Frank, Dufour, Jean-Francois, Haller, Dirk, Murray, Peter J., Heeren, Ron, Zehn, Dietmar, Böttcher, Jan P., Heikenwälder, Mathias, and Knolle, Percy A.

Published
2021
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12. Inhibition of LTβR signalling activates WNT-induced regeneration in lung

Author

Conlon, Thomas M., John-Schuster, Gerrit, Heide, Danijela, Pfister, Dominik, Lehmann, Mareike, Hu, Yan, Ertüz, Zeynep, Lopez, Martin A., Ansari, Meshal, Strunz, Maximilian, Mayr, Christoph, Angelidis, Ilias, Ciminieri, Chiara, Costa, Rita, Kohlhepp, Marlene Sophia, Guillot, Adrien, Günes, Gizem, Jeridi, Aicha, Funk, Maja C., Beroshvili, Giorgi, Prokosch, Sandra, Hetzer, Jenny, Verleden, Stijn E., Alsafadi, Hani, Lindner, Michael, Burgstaller, Gerald, Becker, Lore, Irmler, Martin, Dudek, Michael, Janzen, Jakob, Goffin, Eric, Gosens, Reinoud, Knolle, Percy, Pirotte, Bernard, Stoeger, Tobias, Beckers, Johannes, Wagner, Darcy, Singh, Indrabahadur, Theis, Fabian J., de Angelis, Martin Hrabé, O’Connor, Tracy, Tacke, Frank, Boutros, Michael, Dejardin, Emmanuel, Eickelberg, Oliver, Schiller, Herbert B., Königshoff, Melanie, Heikenwalder, Mathias, and Yildirim, Ali Önder

Published
2020
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13. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Author

Crouchet, Emilie, Bandiera, Simonetta, Fujiwara, Naoto, Li, Shen, El Saghire, Hussein, Fernández-Vaquero, Mirian, Riedl, Tobias, Sun, Xiaochen, Hirschfield, Hadassa, Jühling, Frank, Zhu, Shijia, Roehlen, Natascha, Ponsolles, Clara, Heydmann, Laura, Saviano, Antonio, Qian, Tongqi, Venkatesh, Anu, Lupberger, Joachim, Verrier, Eloi R., Sojoodi, Mozhdeh, Oudot, Marine A., Duong, François H. T., Masia, Ricard, Wei, Lan, Thumann, Christine, Durand, Sarah C., González-Motos, Victor, Heide, Danijela, Hetzer, Jenny, Nakagawa, Shigeki, Ono, Atsushi, Song, Won-Min, Higashi, Takaaki, Sanchez, Roberto, Kim, Rosa S., Bian, C. Billie, Kiani, Karun, Croonenborghs, Tom, Subramanian, Aravind, Chung, Raymond T., Straub, Beate K., Schuppan, Detlef, Ankavay, Maliki, Cocquerel, Laurence, Schaeffer, Evelyne, Goossens, Nicolas, Koh, Anna P., Mahajan, Milind, Nair, Venugopalan D., Gunasekaran, Ganesh, Schwartz, Myron E., Bardeesy, Nabeel, Shalek, Alex K., Rozenblatt-Rosen, Orit, Regev, Aviv, Felli, Emanuele, Pessaux, Patrick, Tanabe, Kenneth K., Heikenwälder, Mathias, Schuster, Catherine, Pochet, Nathalie, Zeisel, Mirjam B., Fuchs, Bryan C., Hoshida, Yujin, and Baumert, Thomas F.

Published
2021
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15. Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice

Author

Elßner, Christin, Goeppert, Benjamin, Longerich, Thomas, Scherr, Anna-Lena, Stindt, Jan, Nanduri, Lahiri Kanth, Rupp, Christian, Kather, Jakob Nikolas, Schmitt, Nathalie, Kautz, Nicole, Breuhahn, Kai, Ismail, Lars, Heide, Danijela, Hetzer, Jenny, García-Beccaria, María, Hövelmeyer, Nadine, Waisman, Ari, Urbanik, Toni, Mueller, Sebastian, Gdynia, Georg, Banales, Jesus M., Roessler, Stephanie, Schirmacher, Peter, Jäger, Dirk, Schölch, Sebastian, Keitel, Verena, Heikenwalder, Mathias, Schulze-Bergkamen, Henning, and Köhler, Bruno Christian

Published
2019
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16. Bovine meat and milk factor protein expression in tumor‐free mucosa of colorectal cancer patients coincides with macrophages and might interfere with patient survival.

Author

Nikitina, Ekaterina, Burk‐Körner, Amelie, Wiesenfarth, Manuel, Alwers, Elizabeth, Heide, Danijela, Tessmer, Claudia, Ernst, Claudia, Krunic, Damir, Schrotz‐King, Petra, Chang‐Claude, Jenny, von Winterfeld, Moritz, Herpel, Esther, Brobeil, Alexander, Brenner, Hermann, Heikenwalder, Mathias, Hoffmeister, Michael, Kopp‐Schneider, Annette, and Bund, Timo

Abstract

Bovine milk and meat factors (BMMFs) are plasmid‐like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co‐markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor‐adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n = 246)], low‐/high‐grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co‐immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor‐adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+/CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD‐adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC‐specific death were increased for higher Rep expression (TMA), with high tumor‐adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF‐specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPAR alpha and PCK1 action in hepatocytes

Author

Gallage, Suchira, primary, Ali, Adnan, additional, Barragan Avila, Jose Efren, additional, Seymen, Nogayhan, additional, Ramadori, Pierluigi, additional, Joerke, Vera, additional, Zizmare, Laimdota, additional, Kosla, Jan, additional, Li, Xin, additional, Focaccia, Enrico, additional, Yousuf, Suhail, additional, Sijmonsma, Tjeerd, additional, Rahbari, Mohammad, additional, Kommoss, Katharina S, additional, Billeter, Adrian, additional, Prokosch, Sandra, additional, Rothermel, Ulrike, additional, Mueller, Florian, additional, Hetzer, Jenny, additional, Heide, Danijela, additional, Machauer, Tim, additional, Malek, Nisar P, additional, Longerich, Thomas, additional, Rose, Adam J, additional, Roth, Susanne, additional, Schwenck, Johannes, additional, Trautwein, Christoph, additional, Karimi, Mohammad M, additional, and Heikenwalder, Mathias, additional

Published
2023
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18. Ribosomal S6 kinase 1 regulates ‘inflammaging’ via the senescence secretome

Author

Gallage, Suchira, primary, Irvine, Elaine E., additional, Pedroni, Silvia M.A., additional, Barragan Avila, Jose Efren, additional, Khadayate, Sanjay, additional, Pombo, Joaquim, additional, Brookes, Sharon, additional, Heide, Danijela, additional, Dharmalingham, Gopuraja, additional, Choudhury, Agharul I., additional, Herranz, Nicolás, additional, Vernia, Santiago, additional, Heikenwalder, Mathias, additional, Gil, Jesús, additional, and Withers, Dominic J., additional

Published
2023
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19. Cardiac glycosides are broad-spectrum senolytics

Author

Guerrero, Ana, Herranz, Nicolás, Sun, Bin, Wagner, Verena, Gallage, Suchira, Guiho, Romain, Wolter, Katharina, Pombo, Joaquim, Irvine, Elaine E., Innes, Andrew J., Birch, Jodie, Glegola, Justyna, Manshaei, Saba, Heide, Danijela, Dharmalingam, Gopuraja, Harbig, Jule, Olona, Antoni, Behmoaras, Jacques, Dauch, Daniel, Uren, Anthony G., Zender, Lars, Vernia, Santiago, Martínez-Barbera, Juan Pedro, Heikenwalder, Mathias, Withers, Dominic J., and Gil, Jesús

Published
2019
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20. HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice

Author

Hoefflin, Rouven, Harlander, Sabine, Schäfer, Silvia, Metzger, Patrick, Kuo, Fengshen, Schönenberger, Désirée, Adlesic, Mojca, Peighambari, Asin, Seidel, Philipp, Chen, Chia-yi, Consenza-Contreras, Miguel, Jud, Andreas, Lahrmann, Bernd, Grabe, Niels, Heide, Danijela, Uhl, Franziska M., Chan, Timothy A., Duyster, Justus, Zeiser, Robert, Schell, Christoph, Heikenwalder, Mathias, Schilling, Oliver, Hakimi, A. Ari, Boerries, Melanie, and Frew, Ian J.

Published
2020
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21. Author Correction: Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Author

Dudek, Michael, Pfister, Dominik, Donakonda, Sainitin, Filpe, Pamela, Schneider, Annika, Laschinger, Melanie, Hartmann, Daniel, Hüser, Norbert, Meiser, Philippa, Bayerl, Felix, Inverso, Donato, Wigger, Jennifer, Sebode, Marcial, Öllinger, Rupert, Rad, Roland, Hegenbarth, Silke, Anton, Martina, Guillot, Adrien, Bowman, Andrew, Heide, Danijela, Müller, Florian, Ramadori, Pierluigi, Leone, Valentina, Garcia-Caceres, Cristina, Gruber, Tim, Seifert, Gabriel, Kabat, Agnieszka M., Mallm, Jan-Philipp, Reider, Simon, Effenberger, Maria, Roth, Susanne, Billeter, Adrian T., Müller-Stich, Beat, Pearce, Edward J., Koch-Nolte, Friedrich, Käser, Rafael, Tilg, Herbert, Thimme, Robert, Boettler, Tobias, Tacke, Frank, Dufour, Jean-Francois, Haller, Dirk, Murray, Peter J., Heeren, Ron, Zehn, Dietmar, Böttcher, Jan P., Heikenwälder, Mathias, and Knolle, Percy A.

Published
2021
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22. Bovine meat and milk factor protein expression in tumor‐free mucosa of colorectal cancer patients coincides with macrophages and might interfere with patient survival

Author

Nikitina, Ekaterina, primary, Burk‐Körner, Amelie, additional, Wiesenfarth, Manuel, additional, Alwers, Elizabeth, additional, Heide, Danijela, additional, Tessmer, Claudia, additional, Ernst, Claudia, additional, Krunic, Damir, additional, Schrotz‐King, Petra, additional, Chang‐Claude, Jenny, additional, von Winterfeld, Moritz, additional, Herpel, Esther, additional, Brobeil, Alexander, additional, Brenner, Hermann, additional, Heikenwalder, Mathias, additional, Hoffmeister, Michael, additional, Kopp‐Schneider, Annette, additional, and Bund, Timo, additional

Published
2023
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23. Publisher Correction: Inhibition of LTβR signalling activates WNT-induced regeneration in lung

Author

Conlon, Thomas M., John-Schuster, Gerrit, Heide, Danijela, Pfister, Dominik, Lehmann, Mareike, Hu, Yan, Ertüz, Zeynep, Lopez, Martin A., Ansari, Meshal, Strunz, Maximilian, Mayr, Christoph, Angelidis, Ilias, Ciminieri, Chiara, Costa, Rita, Kohlhepp, Marlene Sophia, Guillot, Adrien, Günes, Gizem, Jeridi, Aicha, Funk, Maja C., Beroshvili, Giorgi, Prokosch, Sandra, Hetzer, Jenny, Verleden, Stijn E., Alsafadi, Hani, Lindner, Michael, Burgstaller, Gerald, Becker, Lore, Irmler, Martin, Dudek, Michael, Janzen, Jakob, Goffin, Eric, Gosens, Reinoud, Knolle, Percy, Pirotte, Bernard, Stoeger, Tobias, Beckers, Johannes, Wagner, Darcy, Singh, Indrabahadur, Theis, Fabian J., de Angelis, Martin Hrabé, O’Connor, Tracy, Tacke, Frank, Boutros, Michael, Dejardin, Emmanuel, Eickelberg, Oliver, Schiller, Herbert B., Königshoff, Melanie, Heikenwalder, Mathias, and Yildirim, Ali Önder

Published
2021
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24. A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity

Author

Roehlen, Natascha, primary, Saviano, Antonio, additional, El Saghire, Houssein, additional, Crouchet, Emilie, additional, Nehme, Zeina, additional, Del Zompo, Fabio, additional, Jühling, Frank, additional, Oudot, Marine A., additional, Durand, Sarah C., additional, Duong, François H. T., additional, Cherradi, Sara, additional, Gonzalez Motos, Victor, additional, Almeida, Nuno, additional, Ponsolles, Clara, additional, Heydmann, Laura, additional, Ostyn, Tessa, additional, Lallement, Antonin, additional, Pessaux, Patrick, additional, Felli, Emanuele, additional, Cavalli, Andrea, additional, Sgrignani, Jacopo, additional, Thumann, Christine, additional, Koutsopoulos, Olga, additional, Fuchs, Bryan C., additional, Hoshida, Yujin, additional, Hofmann, Maike, additional, Vyberg, Mogens, additional, Viuff, Birgitte Martine, additional, Galsgaard, Elisabeth D., additional, Elson, Greg, additional, Toso, Alberto, additional, Meyer, Markus, additional, Iacone, Roberto, additional, Schweighoffer, Tamas, additional, Teixeira, Geoffrey, additional, Moll, Solange, additional, De Vito, Claudio, additional, Roskams, Tania, additional, Davidson, Irwin, additional, Heide, Danijela, additional, Heikenwälder, Mathias, additional, Zeisel, Mirjam B., additional, Lupberger, Joachim, additional, Mailly, Laurent, additional, Schuster, Catherine, additional, and Baumert, Thomas F., additional

Published
2022
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25. Comparison of HAV and HCV infectionsin vivoandin vitroreveals distinct patterns of innate immune evasion and activation

Author

Colasanti, Ombretta, primary, Burm, Rani, additional, Huang, Hao-En, additional, Riedl, Tobias, additional, Traut, Jannik, additional, Gillich, Nadine, additional, Li, Teng-Feng, additional, Corneillie, Laura, additional, Faure-Dupuy, Suzanne, additional, Grünvogel, Oliver, additional, Heide, Danijela, additional, Lee, Ji-Young, additional, Tran, Cong Si, additional, Merle, Uta, additional, Chironna, Maria, additional, Vondran, Florian F.W., additional, Esser-Nobis, Katharina, additional, Binder, Marco, additional, Bartenschlager, Ralf, additional, Heikenwälder, Mathias, additional, Meuleman, Philip, additional, and Lohmann, Volker, additional

Published
2022
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26. Peroxiredoxin 2 is a target for hepatocellular carcinoma chemoprevention

Author

Crouchet, Emilie, primary, Schaeffer, Eugénie, additional, El Saghire, Hussein, additional, Fujiwara, Naoto, additional, Jühling, Frank, additional, Oudot, Marine, additional, Ponsolles, Clara, additional, Brignon, Nicolas, additional, Durand, Sarah, additional, Parnot, Marie, additional, Heide, Danijela, additional, Hetzer, Jenny, additional, Heikenwälder, Mathias, additional, Felli, Emanuele, additional, Pessaux, Patrick, additional, Pochet, Nathalie, additional, Hoshida, Yujin, additional, Mailly, Laurent, additional, Baumert, Thomas, additional, and Schuster, Catherine, additional

Published
2022
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27. Mixed HCC-CCA originates from hepatic progenitor cells, is dependent on IL6 singling and is ablated by senolytic agents

Author

Rosenberg, Nofar, primary, Van Haele, Matthias, additional, Beccaria, Maria Garcia, additional, Fernández-Vaquero, Mirian, additional, Heide, Danijela, additional, Barashi, Neta, additional, Peled, Amnon, additional, Nevo, Yuval, additional, Elgavish, Shrona, additional, Schmist-Arras, Dirk, additional, Edler, Hanan, additional, Simerzin, Alina, additional, Shoshkes-Carmel, Michal, additional, Kaestner, Klaus, additional, Giladi, Hilla, additional, Rose-John, Stefan, additional, Roskams, Tania, additional, Heikenwälder, Mathias, additional, and Galun, Eithan, additional

Published
2022
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30. Corrigendum to “Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation” [J Hepatol (2023) 645–656]

Author

Colasanti, Ombretta, Burm, Rani, Huang, Hao-En, Riedl, Tobias, Traut, Jannik, Gillich, Nadine, Li, Teng-Feng, Corneillie, Laura, Faure-Dupuy, Suzanne, Grünvogel, Oliver, Heide, Danijela, Lee, Ji-Young, Tran, Cong Si, Merle, Uta, Chironna, Maria, Vondran, Florian F.W., Esser-Nobis, Katharina, Binder, Marco, Bartenschlager, Ralf, Heikenwälder, Mathias, Meuleman, Philip, and Lohmann, Volker

Published
2024
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31. Therapeutic Effects of Inhibition of Sphingosine-1-Phosphate Signaling in HIF-2α Inhibitor-Resistant Clear Cell Renal Cell Carcinoma

Author

Hoefflin, Rouven, primary, Harlander, Sabine, additional, Abhari, Behnaz A., additional, Peighambari, Asin, additional, Adlesic, Mojca, additional, Seidel, Philipp, additional, Zodel, Kyra, additional, Haug, Stefan, additional, Göcmen, Burulca, additional, Li, Yong, additional, Lahrmann, Bernd, additional, Grabe, Niels, additional, Heide, Danijela, additional, Boerries, Melanie, additional, Köttgen, Anna, additional, Heikenwalder, Mathias, additional, and Frew, Ian J., additional

Published
2021
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32. Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis

Author

Singhal, Mahak, primary, Gengenbacher, Nicolas, additional, Abdul Pari, Ashik Ahmed, additional, Kamiyama, Miki, additional, Hai, Ling, additional, Kuhn, Bianca J., additional, Kallenberg, David M., additional, Kulkarni, Shubhada R., additional, Camilli, Carlotta, additional, Preuß, Stephanie F., additional, Leuchs, Barbara, additional, Mogler, Carolin, additional, Espinet, Elisa, additional, Besemfelder, Eva, additional, Heide, Danijela, additional, Heikenwalder, Mathias, additional, Sprick, Martin R., additional, Trumpp, Andreas, additional, Krijgsveld, Jeroen, additional, Schlesner, Matthias, additional, Hu, Junhao, additional, Moss, Stephen E., additional, Greenwood, John, additional, and Augustin, Hellmut G., additional

Published
2021
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33. Hypoxia‐Inducible Factor 1 Alpha–Mediated RelB/APOBEC3B Down‐regulation Allows Hepatitis B Virus Persistence

Author

Riedl, Tobias, primary, Faure‐Dupuy, Suzanne, additional, Rolland, Maude, additional, Schuehle, Svenja, additional, Hizir, Zohier, additional, Calderazzo, Silvia, additional, Zhuang, Xiaodong, additional, Wettengel, Jochen, additional, Lopez, Martin Alexander, additional, Barnault, Romain, additional, Mirakaj, Valbona, additional, Prokosch, Sandra, additional, Heide, Danijela, additional, Leuchtenberger, Corinna, additional, Schneider, Martin, additional, Heßling, Bernd, additional, Stottmeier, Benjamin, additional, Wessbecher, Isabel M., additional, Schirmacher, Peter, additional, McKeating, Jane A, additional, Protzer, Ulrike, additional, Durantel, David, additional, Lucifora, Julie, additional, Dejardin, Emmanuel, additional, and Heikenwalder, Mathias, additional

Published
2021
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34. HIF1α-mediated RelB/APOBEC3B downregulation allows Hepatitis B Virus persistence

Author

Riedl, Tobias, Faure-Dupuy, Suzanne, Rolland, Maude, Schuehle, Svenja, Hizir, Zohier, Calderazzo, Silvia, Zhuang, Xiaodong, Wettengel, Jochen, Lopez, Martin Alexander, Barnault, Romain, Mirakaj, Valbona, Prokosch, Sandra, Heide, Danijela, Leuchtenbergeg, Corinna, Schneider, Martin, Heßling, Bernd, Stottmeier, Benjamin, Wessbecher, Isabel, Schirmacher, Peter, Mckeating, Jane, Protzer, Ulrike, Durantel, David, Lucifora, Julie, Dejardin, Emmanuel, Heikenwalder, Mathias, Faure‐Dupuy, Suzanne, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Hepatitis B virus, reservoir, Down-Regulation, Article, NF-κB, Cell Line, Minor Histocompatibility Antigens, Mice, Hepatitis B, Chronic, Lymphotoxin beta Receptor, Cytidine Deaminase, Animals, Humans, RNA, Messenger, HIF1α, Hypoxia, Microbial Viability, Transcription Factor RelB, Hypoxia-Inducible Factor 1, alpha Subunit, Hif1α, Hepatitis B Virus, Nf-κb, Cccdna, Reservoir, Amino Acids, Dicarboxylic, Liver, Gene Knockdown Techniques, cccDNA, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, DNA, Circular
Abstract

Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia-inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization.We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT-qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up-regulation and -mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator.In conclusion, inhibiting HIF1α expression or stabilization represents an anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.

Published
2021
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35. Intercrypt sentinel macrophages tune antibacterial NF-kappa B responses in gut epithelial cells via TNF

Author

Hausmann, Annika, Felmy, Boas, Kunz, Leo, Kroon, Sanne, Berthold, Dorothee Lisa, Ganz, Giverny, Sandu, Ioana, Nakamura, Toshihiro, Zangger, Nathan Sebastien, Zhang, Yang, Dolowschiak, Tamas, Fattinger, Stefan Alexander, Furter, Markus, Mueller-Hauser, Anna Angelika, Barthel, Manja, Vlantis, Katerina, Wachsmuth, Laurens, Kisielow, Jan, Tortola, Luigi, Heide, Danijela, Heikenwaelder, Mathias, Oxenius, Annette, Kopf, Manfred, Schroeder, Timm, Pasparakis, Manolis, Sellin, Mikael Erik, Hardt, Wolf-Dietrich, Hausmann, Annika, Felmy, Boas, Kunz, Leo, Kroon, Sanne, Berthold, Dorothee Lisa, Ganz, Giverny, Sandu, Ioana, Nakamura, Toshihiro, Zangger, Nathan Sebastien, Zhang, Yang, Dolowschiak, Tamas, Fattinger, Stefan Alexander, Furter, Markus, Mueller-Hauser, Anna Angelika, Barthel, Manja, Vlantis, Katerina, Wachsmuth, Laurens, Kisielow, Jan, Tortola, Luigi, Heide, Danijela, Heikenwaelder, Mathias, Oxenius, Annette, Kopf, Manfred, Schroeder, Timm, Pasparakis, Manolis, Sellin, Mikael Erik, and Hardt, Wolf-Dietrich

Abstract

Intestinal epithelial cell (IEC) NF-kappa B signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-kappa B activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-kappa B signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-kappa B responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.

Published
2021

36. Publisher Correction: Inhibition of LTβR signalling activates WNT-induced regeneration in lung

Author

Conlon, Thomas M., primary, John-Schuster, Gerrit, additional, Heide, Danijela, additional, Pfister, Dominik, additional, Lehmann, Mareike, additional, Hu, Yan, additional, Ertüz, Zeynep, additional, Lopez, Martin A., additional, Ansari, Meshal, additional, Strunz, Maximilian, additional, Mayr, Christoph, additional, Angelidis, Ilias, additional, Ciminieri, Chiara, additional, Costa, Rita, additional, Kohlhepp, Marlene Sophia, additional, Guillot, Adrien, additional, Günes, Gizem, additional, Jeridi, Aicha, additional, Funk, Maja C., additional, Beroshvili, Giorgi, additional, Prokosch, Sandra, additional, Hetzer, Jenny, additional, Verleden, Stijn E., additional, Alsafadi, Hani, additional, Lindner, Michael, additional, Burgstaller, Gerald, additional, Becker, Lore, additional, Irmler, Martin, additional, Dudek, Michael, additional, Janzen, Jakob, additional, Goffin, Eric, additional, Gosens, Reinoud, additional, Knolle, Percy, additional, Pirotte, Bernard, additional, Stoeger, Tobias, additional, Beckers, Johannes, additional, Wagner, Darcy, additional, Singh, Indrabahadur, additional, Theis, Fabian J., additional, de Angelis, Martin Hrabé, additional, O’Connor, Tracy, additional, Tacke, Frank, additional, Boutros, Michael, additional, Dejardin, Emmanuel, additional, Eickelberg, Oliver, additional, Schiller, Herbert B., additional, Königshoff, Melanie, additional, Heikenwalder, Mathias, additional, and Yildirim, Ali Önder, additional

Published
2020
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37. Single cell RNA-seq of patient liver tissues uncover HRH2+/CLEC5a high/macro low macrophages as therapeutic target for the treatment of liver fibrosis and cancer prevention

Author

Crouchet, Emilie, primary, Bandiera, Simonetta, additional, Fujiwara, Naoto, additional, Li, Shen, additional, El Saghire, Hussein, additional, Sun, Xiaochen, additional, Hirschfield, Hadassa, additional, Roehlen, Natascha, additional, Jühling, Frank, additional, Saviano, Antonio, additional, Gonzalez-Motos, Victor, additional, Venkatesh, Anu, additional, Ponsolles, Clara, additional, Lupberger, Joachim, additional, Duong, François H.T., additional, Zhu, Shijia, additional, Sojoodi, Mozhdeh, additional, Masia, Ricard, additional, Wei, Lan, additional, Oudot, Marine, additional, Durand, Sarah, additional, Nakagawa, Shigeki, additional, Ono, Atsushi, additional, Song, Won-Min, additional, Higashi, Takaaki, additional, Kim, Rosa S., additional, Bian, C Billie, additional, Croonenborghs, Tom, additional, Chung, Raymond, additional, Heide, Danijela, additional, Hetzer, Jenny, additional, Straub, Beate, additional, Schuppan, Detlef, additional, Koh, Anna P., additional, Mahajan, Milind, additional, Heikenwalder, Mathias, additional, Felli, Emanuele, additional, Pessaux, Patrick, additional, Tanabe, Kenneth K., additional, Schuster, Catherine, additional, Pochet, Nathalie, additional, Zeisel, Mirjam, additional, Fuchs, Bryan C., additional, Hoshida, Yujin, additional, and Baumert, Thomas, additional

Published
2020
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38. A human liver cell-based system modeling a clinical prognostic liver signature combined with single cell RNA-seq for discovery of novel liver disease therapeutics

Author

Crouchet, Emilie, primary, Bandiera, Simonetta, additional, Fujiwara, Naoto, additional, Li, Shen, additional, El Saghire, Hussein, additional, Sun, Xiaochen, additional, Hirschfield, Hadassa, additional, Roehlen, Natascha, additional, Jühling, Frank, additional, Saviano, Antonio, additional, Gonzalez-Motos, Victor, additional, Venkatesh, Anu, additional, Ponsolles, Clara, additional, Verrier, Eloi, additional, Van Renne, Nicolaas, additional, Lupberger, Joachim, additional, Thumann, Christine, additional, Duong, François H.T., additional, Zhu, Shijia, additional, Sojoodi, Mozhdeh, additional, Masia, Ricard, additional, Wei, Lan, additional, Oudot, Marine, additional, Durand, Sarah, additional, Nakagawa, Shigeki, additional, Ono, Atsushi, additional, Song, Won-Min, additional, Higashi, Takaaki, additional, Sanchez, Roberto, additional, Kim, Rosa S., additional, Bian, C. Billie, additional, Kiani, Karun, additional, Croonenborghs, Tom, additional, Subramanian, Aravind, additional, Chung, Raymond, additional, Heide, Danijela, additional, Hetzer, Jenny, additional, Straub, Beate, additional, Schuppan, Detlef, additional, Ankavay, Maliki, additional, Cocquerel, Laurence, additional, Schaeffer, Evelyne, additional, Goossens, Nicolas, additional, Koh, Anna P., additional, Mahajan, Milind, additional, Nair, Venugopalan D., additional, Gunasekaran, Ganesh, additional, Schwartz, Myron, additional, Bardeesy, Nabeel, additional, Shalek, Alex K., additional, Rozenblatt-Rosen, Orit, additional, Regev, Aviv, additional, Heikenwalder, Mathias, additional, Felli, Emanuele, additional, Pessaux, Patrick, additional, Tanabe, Kenneth K., additional, Schuster, Catherine, additional, Pochet, Nathalie, additional, Zeisel, Mirjam, additional, Fuchs, Bryan C., additional, Hoshida, Yujin, additional, and Baumert, Thomas, additional

Published
2020
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39. Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention

Author

O'Connor, Tracy, primary, Zhou, Xiaolan, additional, Kosla, Jan, additional, Adili, Arlind, additional, Garcia Beccaria, Maria, additional, Kotsiliti, Elena, additional, Pfister, Dominik, additional, Johlke, Anna-Lena, additional, Sinha, Ankit, additional, Sankowski, Roman, additional, Schick, Markus, additional, Lewis, Richard, additional, Dokalis, Nikolaos, additional, Seubert, Bastian, additional, Höchst, Bastian, additional, Inverso, Donato, additional, Heide, Danijela, additional, Zhang, Wenlong, additional, Weihrich, Petra, additional, Manske, Katrin, additional, Wohlleber, Dirk, additional, Anton, Martina, additional, Hoellein, Alexander, additional, Seleznik, Gitta, additional, Bremer, Juliane, additional, Bleul, Sabine, additional, Augustin, Hellmut G., additional, Scherer, Florian, additional, Koedel, Uwe, additional, Weber, Achim, additional, Protzer, Ulrike, additional, Förster, Reinhold, additional, Wirth, Thomas, additional, Aguzzi, Adriano, additional, Meissner, Felix, additional, Prinz, Marco, additional, Baumann, Bernd, additional, Höpken, Uta E., additional, Knolle, Percy A., additional, von Baumgarten, Louisa, additional, Keller, Ulrich, additional, and Heikenwalder, Mathias, additional

Published
2019
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40. PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells

Author

Georgilis, Athena, primary, Klotz, Sabrina, additional, Hanley, Christopher J., additional, Herranz, Nicolas, additional, Weirich, Benedikt, additional, Morancho, Beatriz, additional, Leote, Ana Carolina, additional, D'Artista, Luana, additional, Gallage, Suchira, additional, Seehawer, Marco, additional, Carroll, Thomas, additional, Dharmalingam, Gopuraja, additional, Wee, Keng Boon, additional, Mellone, Marco, additional, Pombo, Joaquim, additional, Heide, Danijela, additional, Guccione, Ernesto, additional, Arribas, Joaquín, additional, Barbosa-Morais, Nuno L., additional, Heikenwalder, Mathias, additional, Thomas, Gareth J., additional, Zender, Lars, additional, and Gil, Jesús, additional

Published
2018
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41. Auto-aggressive CXCR6+CD8 T cells cause liver immune pathology in NASH

Author

Dudek, Michael, Pfister, Dominik, Donakonda, Sainitin, Filpe, Pamela, Schneider, Annika, Laschinger, Melanie, Hartmann, Daniel, Hüser, Norbert, Meiser, Philippa, Bayerl, Felix, Inverso, Donato, Wigger, Jennifer, Sebode, Marcial, Öllinger, Rupert, Rad, Roland, Hegenbarth, Silke, Anton, Martina, Guillot, Adrien, Bowman, Andrew, Heide, Danijela, Müller, Florian, Ramadori, Pierluigi, Leone, Valentina, Garcia-Caceres, Cristina, Gruber, Tim, Seifert, Gabriel, Kabat, Agnieszka M., Mallm, Jan-Philipp, Reider, Simon, Effenberger, Maria, Roth, Susanne, Billeter, Adrian T., Müller-Stich, Beat, Pearce, Edward J., Koch-Nolte, Friedrich, Käser, Rafael, Tilg, Herbert, Thimme, Robert, Boettler, Tobias, Tacke, Frank, Dufour, Jean-Francois, Haller, Dirk, Murray, Peter J., Heeren, Ron, Zehn, Dietmar, Böttcher, Jan P., Heikenwälder, Mathias, and Knolle, Percy A.

Abstract

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Published
2021
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43. Selective Blocking of TNF Receptor 1 Attenuates Peritoneal Dialysis Fluid Induced Inflammation of the Peritoneum in Mice

Author

Kälble, Florian, primary, Damaske, Janine, additional, Heide, Danijela, additional, Arnold, Iris, additional, Richter, Fabian, additional, Maier, Olaf, additional, Eisel, Ulrich, additional, Scheurich, Peter, additional, Pfizenmaier, Klaus, additional, Zeier, Martin, additional, Schwenger, Vedat, additional, and Ranzinger, Julia, additional

Published
2016
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45. Author Correction: Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.

Author

Dudek, Michael, Pfister, Dominik, Donakonda, Sainitin, Filpe, Pamela, Schneider, Annika, Laschinger, Melanie, Hartmann, Daniel, Hüser, Norbert, Meiser, Philippa, Bayerl, Felix, Inverso, Donato, Wigger, Jennifer, Sebode, Marcial, Öllinger, Rupert, Rad, Roland, Hegenbarth, Silke, Anton, Martina, Guillot, Adrien, Bowman, Andrew, and Heide, Danijela

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03568-2. [ABSTRACT FROM AUTHOR]

Published
2021
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46. Author Correction: Auto-aggressive CXCR6+CD8 T cells cause liver immune pathology in NASH

Author

Dudek, Michael, Pfister, Dominik, Donakonda, Sainitin, Filpe, Pamela, Schneider, Annika, Laschinger, Melanie, Hartmann, Daniel, Hüser, Norbert, Meiser, Philippa, Bayerl, Felix, Inverso, Donato, Wigger, Jennifer, Sebode, Marcial, Öllinger, Rupert, Rad, Roland, Hegenbarth, Silke, Anton, Martina, Guillot, Adrien, Bowman, Andrew, Heide, Danijela, Müller, Florian, Ramadori, Pierluigi, Leone, Valentina, Garcia-Caceres, Cristina, Gruber, Tim, Seifert, Gabriel, Kabat, Agnieszka M., Mallm, Jan-Philipp, Reider, Simon, Effenberger, Maria, Roth, Susanne, Billeter, Adrian T., Müller-Stich, Beat, Pearce, Edward J., Koch-Nolte, Friedrich, Käser, Rafael, Tilg, Herbert, Thimme, Robert, Boettler, Tobias, Tacke, Frank, Dufour, Jean-Francois, Haller, Dirk, Murray, Peter J., Heeren, Ron, Zehn, Dietmar, Böttcher, Jan P., Heikenwälder, Mathias, and Knolle, Percy A.

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03568-2.

Published
2021
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47. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz De Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias

Subjects
Male, Carcinoma, Hepatocellular, Carcinogenesis, Tumor Necrosis Factor-alpha, Liver Neoplasms, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, digestive system diseases, B7-H1 Antigen, 3. Good health, Mice, Liver, Non-alcoholic Fatty Liver Disease, Disease Progression, Animals, Humans, Immunotherapy
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

48. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz de Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-François, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias

Subjects
610 Medicine & health, digestive system diseases, 3. Good health
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

49. Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF

Author

Hausmann, Annika, Felmy, Boas, Kunz, Leo, Kroon, Sanne, Berthold, Dorothée L., Ganz, Giverny, Sandu, Ioana, Nakamura, Toshihiro, Zangger, Nathan Sébastien, Zhang, Yang, Dolowschiak, Tamas, Fattinger, Stefan A., Furter, Markus, Müller-Hauser, Anna A., Barthel, Manja, Vlantis, Katerina, Wachsmuth, Laurens, Kisielow, Jan, Tortola, Luigi, Heide, Danijela, Heikenwälder, Mathias, Oxenius, Annette, Kopf, Manfred, Schroeder, Timm, Pasparakis, Manolis, Sellin, Mikael E., and Hardt, Wolf-Dietrich

Subjects
digestive system, 3. Good health
Abstract

Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers., Journal of Experimental Medicine, 218 (11), ISSN:0022-1007, ISSN:1540-0069, ISSN:1540-9538

50. TNF Signaling in Peritoneal Mesothelial Cells: Pivotal Role of cFLIP L .

Author

Lüdemann WM, Heide D, Kihm L, Zeier M, Scheurich P, Schwenger V, and Ranzinger J

Subjects
Apoptosis, Blotting, Western, CASP8 and FADD-Like Apoptosis Regulating Protein biosynthesis, Cell Survival, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Epithelial Cells pathology, Flow Cytometry, Humans, Inflammation metabolism, Inflammation pathology, Microscopy, Fluorescence, Omentum pathology, RNA, Messenger genetics, Receptors, Tumor Necrosis Factor, Type I biosynthesis, Signal Transduction, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Epithelial Cells metabolism, Gene Expression Regulation, Inflammation genetics, Omentum metabolism, Peritoneal Dialysis adverse effects, Receptors, Tumor Necrosis Factor, Type I genetics
Abstract

♦ BACKGROUND: Peritoneal dialysis (PD) coincides with high concentrations of proinflammatory cytokines, such as tumor necrosis factor (TNF), in the peritoneal cavity. During treatment, chronic inflammatory processes lead to damage of the peritoneal membrane and a subsequent ultrafiltration failure. Human peritoneal mesothelial cells (HPMCs) play a central role as mediators and targets of PD-related inflammatory changes. Although TNF Receptor 1 (TNFR1) is expressed in high numbers on the cells, TNF-induced apoptosis is inhibited. Here, the underlying molecular mechanisms of TNFR1 signaling in HPMCs are investigated. ♦ METHODS: Human peritoneal mesothelial cells were isolated from the omentum of healthy donors and the dialysis solution of PD patients. Flow cytometry was applied to determine cell surface expression of TNFR1 on HPMCS from healthy donors in absence or presence of TNF or PD fluid (PDF) and were compared to TNFR1 expression on cells from PD patients. To investigate TNFR1-mediated signaling, HPMCs were treated with PDF or TNF, and expression patterns of proteins involved in the TNFR1 signaling pathway were assessed by western blot. ♦ RESULTS: Incubation with PDF led to a significant up-regulation of TNFR1 on the cell surface correlating with elevated TNFR1 numbers on HPMCs from PD patients. Investigations of underlying molecular mechanisms of TNFR1 signaling showed that PDF affects TNFR1 signaling at the proapoptotic signaling pathway by upregulation of IκBα and downregulation of cFLIP L . In contrast, TNF exclusively induces the activation of NFκB by an increase of phosphorylated IκBα. ♦ CONCLUSIONS: Novel and relevant insights into the mechanisms of TNFR1-mediated signaling in HPMCs with an impact on our understanding of PD-associated damage of the peritoneal membrane are shown., (Copyright © 2017 International Society for Peritoneal Dialysis.)

Published
2017
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