Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn’s disease and regulate Th1/Th17 cell responses

Abstract

Increased T helper (Th)1/Th17 immune responses are a hallmark of Crohn’s disease (CD) immunopathogenesis. CD90+ (myo-)fibroblasts (MFs) are abundant cells in the normal (N) intestinal mucosa contributing to mucosal tolerance via suppression of Th1 cell activity through cell surface membrane-bound PD-L1 (mPD-L1). CD-MFs have a decreased level of mPD-L1. Consequently, mPD-L1-mediated suppression of Th1 cells by CD-MFs is decreased, yet the mechanism responsible for the reduction in mPDL-1 is unknown. Increased expression of matrix metalloproteinases (MMPs) has been reported in CD. Herein we observed that when compared to N- and ulcerative colitis (UC)-MFs, CD-MFs increase in LPS-inducible levels of MMP-7 and -9 with a significant increase in both basal and inducible MMP-10. A similar pattern of MMP expression was observed in the CD-inflamed mucosa. Treatment of N-MFs with a combination of recombinant human MMP-7, -9 and -10 significantly decreased mPD-L1. In contrast, inhibition of MMP activity with MMP inhibitors or anti-MMP-10 neutralizing antibodies restores mPD-L1 on CD-MFs. CD-MFs demonstrated reduced capacity to suppress Th1 and Th17 responses from activated CD4+ T cells. By contrast, supplementation of the CD-MF:T-cell co-cultures with MMP inhibitors or anti-MMP neutralizing antibodies restored the CD-MF-mediated suppression. Our data suggest that (i) increased MMP-10 expression by CD-MFs and concomitant cleavage of PD-L1 from the surface of CD-MFs are likely to be one of the factors contributing to the decrease of mPD-L1-mediated suppression of Th1/Th17 cells in CD; and (ii) MMPs are likely to have a significant role in the intestinal mucosal immune responses.

Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes

“…Polymorphisms in these genes have been associated to higher risk for T1D development ( 68 , 69 ), and mild hyperglycemia induces their upregulation and that of other genes identified in the same pathway ( 70 ). There was also activation of matrix metalloproteinases, which is a potentially relevant mechanism in T1D since matrix metalloproteinases can cleave membrane-bound PDL1 present on the cell surface and thus regulate T-cell responses ( 71 ).…”

Digestive Inflammation: Role of Proteolytic Dysregulation

“…Considering that (i) in vitro PGP induces the release of MMP-9 and CXCL8 from neutrophils and (ii) neutrophils from IBD patients secrete more MMP-8 and MMP-9 under unstimulated conditions and have increased migration capabilities toward CXCL8 than neutrophils from healthy patients, they form elements of a vicious circle of sustained neutrophilic inflammation in IBD. Recently, the contribution of MMP-10 and, to some extent, MMP-9 and -7 to CD, has been highlighted through the identification of their action on programmed death-ligand 1 (PD-L1), an immune regulatory molecule present in myofibroblasts (MFs) [ 23 ]. In healthy conditions, MFs can suppress T-helper 1 (Th1)- and T-helper 17 (Th17)-type responses through the presence of PD-L1 molecules at their surface.…”

Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?

“…Moreover, Smillie et al showed the upregulation of genes encoding for IL-11, IL-25, IL-13RA2, and fibroblast activation protein (FAP) in activated fibroblasts from UC patients [ 76 ]. Another example of activated fibroblasts’ modulation of the immune response is that fibroblasts isolated from CD patients produce a high level of MMP10 leading to the decrease of the membrane-bound form of the immune-negative regulator PDL1 at their surface and, consequently, an increase of the immune activity [ 77 ]. Strikingly, this increased expression of MMP10 is not observed in UC patients.…”