Tim-3 promotes homeostasis of ulcerative colitis by inhibiting M1 macrophage polarization (INC6P.308)

Abstract

Abstract Abstract We previously found that Tim-3 is involved in the physiopathology of inflammatory bowel diseases (IBD). However, the underlying mechanisms remain to be determined. Here we further demonstrated that Tim-3 contributes to the homeostasis of ulcerative colitis (UC), one type of IBD, by suppressing the polarization of pathogenic M1 macrophages. Downregulation or blockade of Tim-3 in UC is associated with biased pro-inflammatory macrophage (M1) response. Adoptive transfer of macrophages silenced of Tim-3 worsened colitis and enhanced inflammation. On the contrary, transgenic expression of Tim-3 attenuated DSS-induced colitis by down-regulating M1 macrophage response. Co-culture macrophages overexpressed of Tim-3 with intestinal lymphocytes decreased pro-inflammatory response. Tim-3 controls the activity of intestinal macrophages partially dependent on TLR-4 signaling, as in TLR-4 knockout mice blockade of Tim-3 pathway resulted in significantly attenuated colitis and decreased M1 macrophage response. Finally we demonstrated that Tim-3 signaling inhibited the phosphorylation of IRF3, a transcriptional factor regulating macrophages polarization. A better understanding of this pathway may shed new light on the pathogenesis of UC and help to find new therapeutic strategy.