IL-13 Promotes Collagen Accumulation in Crohn’s Disease Fibrosis by Down-Regulation of Fibroblast MMP Synthesis: A Role for Innate Lymphoid Cells?

Abstract

BackgroundFibrosis is a serious consequence of Crohn’s disease (CD), often necessitating surgical resection. We examined the hypothesis that IL-13 may promote collagen accumulation within the CD muscle microenvironment.MethodsFactors potentially modulating collagen deposition were examined in intestinal tissue samples from fibrotic (f) CD and compared with cancer control (C), ulcerative colitis (UC) and uninvolved (u) CD. Mechanisms attributable to IL-13 were analysed using cell lines derived from uninvolved muscle tissue and tissue explants.ResultsIn fCD muscle extracts, collagen synthesis was significantly increased compared to other groups, but MMP-2 was not co-ordinately increased. IL-13 transcripts were highest in fCD muscle compared to muscle from other groups. IL-13 receptor (R) α1 was expressed by intestinal muscle smooth muscle, nerve and KIR+ cells. Fibroblasts from intestinal muscle expressed Rα1, phosphorylated STAT6 in response to IL-13, and subsequently down-regulated MMP-2 and TNF-α-induced MMP-1 and MMP-9 synthesis. Cells with the phenotype KIR+CD45+CD56+/−CD3− were significantly increased in fCD muscle compared to all other groups, expressed Rα1 and membrane IL-13, and transcribed high levels of IL-13. In explanted CD muscle, these cells did not phosphorylate STAT6 in response to exogenous IL-13.ConclusionsThe data indicate that in fibrotic intestinal muscle of Crohn’s patients, the IL-13 pathway is stimulated, involving a novel population of infiltrating IL-13Rα1+, KIR+ innate lymphoid cells, producing IL-13 which inhibits fibroblast MMP synthesis. Consequently, matrix degradation is down-regulated and this leads to excessive collagen deposition.

Absence of a role for interleukin‐13 in inflammatory bowel disease

“…Conversely, IL-1β and collagen levels in the supernatants and TGF-β1 transcripts in the homogenates of cultured explants were markedly higher in strictured CD. Our data are in contrast with the observation by Bailey et al [24] that IL-13 mRNA is overexpressed in the lysates of fibrotic intestinal muscle of CD patients compared with that in control subjects, however this discrepancy may be explained by post-transcriptional modifications which may ultimately determine IL-13 protein level.Given the lack of information on the gut mucosal distribution of IL-13Rs, we investigated their expression by different LPMC subtypes in inflammatory bowel disease and control mucosa. In particular, since IL-13 can bind to IL-13Rα2 or to the heterodimer formed by IL-13Rα1 and IL-4Rα [26], we assessed by flow cytometry the expression of IL-4Rα, IL-13Rα1 and IL-13Rα2 on the surface and in the cytoplasm of T cells (CD3 + cells) and macrophages (CD68 + cells) from healthy mucosa of control subjects, from inflamed UC and CD mucosa, and from the mucosa overlying CD strictures and CD mucosa above non-strictured areas.…”

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease

“…Conversely, other studies have suggested that ILC2s and eosinophils are contributing factors to CD progression through an IL-13 dependent accumulation of matrix-producing fibroblasts (16,17). Thus, there is evidence to support both Th2 and Th17 responses in the pathology of CD.…”

The two sides of the coin: Similarities and differences in the pathomechanisms of fistulas and stricture formations in irritable bowel disease

“…Interestingly, increased levels of IL-13 in the fibrotic intestine of CD patients are produced by a previously not described population of cells expressing high levels of IL-13Ra 1 and IL-13 in the muscle layer of CD intestine. 39 The phenotype of these cells (KIR…”