Wahida, Adam and Mueller, Madeleine and Hiergeist, Andreas and Popper, Bastian and Steiger, Katja and Branca, Caterina and Tschurtschenthaler, Markus and Engleitner, Thomas and Donakonda, Sainitin and De Coninck, Jordy and Oellinger, Rupert and Pfautsch, Marie K. and Mueller, Nicole and Silva, Miguel and Usluer, Sinem and Orberg, Erik Thiele and Boettcher, Jan P. and Pfarr, Nicole and Anton, Martina and Slotta-Huspenina, Julia B. and Nerlich, Andreas G. and Madl, Tobias and Basic, Marijana and Bleich, Andre and Berx, Geert and Ruland, Jurgen and Knolle, Percy A. and Rad, Roland and Adolph, Timon E. and Vandenabeele, Peter and Kanegane, Hirokazu and Gessner, Andre and Jost, Philipp J. and Yabal, Monica (2021) XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells. SCIENCE IMMUNOLOGY, 6 (65): eabf7235. ISSN 2470-9468
Full text not available from this repository. (Request a copy)Abstract
Deficiency in X-linked inhibitor of apoptosis protein (XIAP) is the cause for X-linked lymphoproliferative syndrome 2 (XLP2). About one-third of these patients suffer from severe and therapy-refractory inflammatory bowel disease (IBD), but the exact cause of this pathogenesis remains undefined. Here, we used XIAP-deficient mice to characterize the mechanisms underlying intestinal inflammation. In Xiap-/- mice, we observed spontaneous terminal ileitis and microbial dysbiosis characterized by a reduction of Clostridia species. We showed that in inflamed mice, both TNF receptor 1 and 2 (TNFR1/2) cooperated in promoting ileitis by targeting TLR5-expressing Paneth cells (PCs) or dendritic cells (DCs). Using intestinal organoids and in vivo modeling, we demonstrated that TLR5 signaling triggered TNF production, which induced PC dysfunction mediated by TNFR1. TNFR2 acted upon lamina propria immune cells. scRNA-seq identified a DC population expressing TLR5, in which Tnfr2 expression was also elevated. Thus, the combined activity of TLR5 and TNFR2 signaling may be responsible for DC loss in lamina propria of Xiap-/- mice. Consequently, both Tnfr1-/-Xiap-/- and Tnfr2-/-Xiap-/- mice were rescued from dysbiosis and intestinal inflammation. Furthermore, RNA-seq of ileal crypts revealed that in inflamed Xiap-/- mice, TLR5 signaling was abrogated, linking aberrant TNF responses with the development of a dysbiosis. Evidence for TNFR2 signaling driving intestinal inflammation was detected in XLP2 patient samples. Together, these data point toward a key role of XIAP in mediating resilience of TLR5-expressing PCs and intestinal DCs, allowing them to maintain tissue integrity and microbiota homeostasis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-NECROSIS-FACTOR; CROHNS-DISEASE; GUT MICROBIOTA; METABOLIC SYNDROME; FACTOR RECEPTOR-1; DEFICIENT MICE; HOST GENETICS; B-CELL; NECROPTOSIS; VARIANTS |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Sep 2022 04:54 |
| Last Modified: | 14 Sep 2022 04:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48135 |
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