| First Author | Ninnemann J | Year | 2022 |
| Journal | Mucosal Immunol | Volume | 15 |
| Issue | 4 | Pages | 698-716 |
| PubMed ID | 35383266 | Mgi Jnum | J:339579 |
| Mgi Id | MGI:7430877 | Doi | 10.1038/s41385-022-00506-x |
| Citation | Ninnemann J, et al. (2022) TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability. Mucosal Immunol 15(4):698-716 |
| abstractText | Successful treatment of chronic inflammatory diseases integrates both the cessation of inflammation and the induction of adequate tissue repair processes. Strikingly, targeting a single proinflammatory cytokine, tumor necrosis factor (TNF), induces both processes in a relevant cohort of inflammatory bowel disease (IBD) patients. However, the molecular mechanisms underlying intestinal repair following TNF blockade during IBD remain elusive. Using a novel humanized model of experimental colitis, we demonstrate that TNF interfered with the tissue repair program via induction of a soluble natural antagonist of IL-22 (IL-22Ra2; IL-22BP) in the colon and abrogated IL-22/STAT3-mediated mucosal repair during colitis. Furthermore, membrane-bound TNF expressed by T cells perpetuated colonic inflammation, while soluble TNF produced by epithelial cells (IECs) induced IL-22BP expression in colonic dendritic cells (DCs) and dampened IL-22-driven restitution of colonic epithelial functions. Finally, TNF induced IL-22BP expression in human monocyte-derived DCs and levels of IL22-BP correlated with TNF in sera of IBD patients. Thus, our data can explain how anti-TNF therapy induces mucosal healing by increasing IL-22 availability and implicates new therapeutic opportunities for IBD. |
