Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas, USA.
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Mucosal Immunol. 2018 Mar;11(2):427-436. doi: 10.1038/mi.2017.53. Epub 2017 Jun 14.
Intestinal fibrosis is a major complication in inflammatory bowel diseases, but the regulatory mechanism that inhibits fibrosis remains unclear. Here we demonstrate that Itchmyofibroblasts express increased amounts of profibrotic collagen type I and α-SMA in response to IL-17. Mechanistically, we demonstrate that Itch directly binds to HIC-5 and targets it for K63-linked ubiquitination to inhibit IL-17-driven intestinal fibrosis. Reconstitution of Itch myofibroblasts with wild-type Itch but not the Itch-C830A mutant normalized the expression of profibrotic genes. Similarly, shRNA-mediated inhibition of HIC-5 normalized the expression of profibrotic gene expression. Thus, we have uncovered a novel mechanism by which Itch negatively regulates intestinal fibrosis.
肠纤维化是炎症性肠病的主要并发症，但抑制纤维化的调节机制尚不清楚。在这里，我们证明 Itch 肌成纤维细胞在受到白介素 17（IL-17）刺激后会表达出更多的促纤维化胶原 I 型和α-SMA。在机制上，我们证明了 Itch 可以直接与 HIC-5 结合，并将其靶向进行 K63 连接的泛素化，从而抑制 IL-17 驱动的肠道纤维化。用野生型 Itch 而不是 Itch-C830A 突变体重建 Itch 肌成纤维细胞可以使促纤维化基因的表达正常化。同样，shRNA 介导的 HIC-5 抑制也可以使促纤维化基因的表达正常化。因此，我们揭示了一种新的机制，即 Itch 负调控肠道纤维化。
