Myeloid differentiation primary response gene (MyD) 88 signalling is not essential for intestinal fibrosis development

Abstract

Dysregulation of the immune response to microbiota is associated with inflammatory bowel disease (IBD), which can trigger intestinal fibrosis. MyD88 is a key component of microbiota signalling but its influence on intestinal fibrosis has not been clarified. Small bowel resections from donor-mice were transplanted subcutaneously into the neck of recipients C57BL/6 B6-MyD88tm1 Aki (MyD88−/−) and C57BL/6-Tg(UBC-green fluorescence protein (GFP))30Scha/J (GFP-Tg). Grafts were explanted up to 21 days after transplantation. Collagen layer thickness was determined using Sirius Red stained slides. In the mouse model of fibrosis collagen deposition and transforming growth factor-beta 1 (TGF-β1) expression was equal in MyD88+/+ and MyD88−/−, indicating that MyD88 was not essential for fibrogenesis. Matrix metalloproteinase (Mmp)9 expression was significantly decreased in grafts transplanted into MyD88−/− recipients compared to MyD88+/+ recipients (0.2 ± 0.1 vs. 153.0 ± 23.1, respectively, p < 0.05), similarly recruitment of neutrophils was significantly reduced (16.3 ± 4.5 vs. 25.4 ± 3.1, respectively, p < 0.05). Development of intestinal fibrosis appears to be independent of MyD88 signalling indicating a minor role of bacterial wall compounds in the process which is in contrast to published concepts and theories. Development of fibrosis appears to be uncoupled from acute inflammation.

Severity of local inflammation does not impact development of fibrosis in mouse models of intestinal fibrosis

“…The exact cause for the initiation and progression of fibrosis in the heterotopic intestinal transplant model is unknown. Graft rejection, ischemia, hypoxia, increased Hif1α and neo-vascularisation could contribute to fibrosis in this animal model 32 , 40 . An excessive synthesis of ECM and activation of intestinal myofibroblasts positive for both vimentin and αSMA, hallmarks in the development of fibrosis, are detectable in the heterotopic transplant animal model of intestinal fibrosis 32 , 41 .…”

“…The immune response to grafts most probably is strain specific. Previously, we observed an increase in neutrophils in the heterotopic transplantation model that may be affected by the immune response to intestinal grafts, rejection, ischemia or hypoxia, which contributes to fibrosis in the animal model but not necessarily to fibrosis in IBD patients 40 . Differences in the microbiome are likely to influence the development of intestinal fibrosis.…”

The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

“…However, bacterial translocation and the pathogen associated molecular pattern [PAMP]-associated signalling is not a prerequisite of fibrosis in this model, as collagen deposition is also increased following transplantation of small bowel from germ-free mice and MyD88-deficient mice. 56 In the heterotopic transplant model, fibrosis is also observed in the absence of B and T cells in RAG2-deficient mice [M. Hausmann, unpublished observations].…”

How to place the duality of specific MMP-9 inhibition for treatment of inflammatory bowel diseases into clinical opportunities?

“…These data reinforce the opportunities for interferences at the regulatory and inhibitory levels. For the acute initiation or progression phases of IBD, the roles of p38 kinase and nuclear factor κB (NFκB) in breakdown of the intestinal barrier by substrate cleavage through MMP-9 ( vide supra ) have been reinforced ( 45 , 47 ). In the chronic phase, when fibrosis is happening, the toll-like receptor (TLR) system with MyD88 as transducer towards the NFκB pathway seems not essential ( 47 ).…”