Tim-3 promotes intestinal homeostasis in DSS colitis by inhibiting M1 polarization of macrophages

- Downregulation of Tim-3 is associated with increased M1 macrophage response in DSS colitis.
- Overexpression of Tim-3 promotes M2 macrophage polarization and attenuates DSS induced colitis.
- Transfer of macrophages with low Tim-3 expression exacerbates colitis and promotes inflammation.
- Macrophages overexpressing Tim-3 mediate suppressed response of intestinal lymphocytes.
- TLR4 is involved in Tim-3 shaped macrophage polarization in DSS colitis.

Tim-3 is involved in the physiopathology of inflammatory bowel disease (IBD), but the underlying mechanism is unknown. Here, we demonstrated that, in mouse with DSS colitis, Tim-3 inhibited the polarization of pathogenic pro-inflammatory M1 macrophages, while Tim-3 downregulation or blockade resulted in an increased M1 response. Adoptive transfer of Tim-3-silenced macrophages worsened DSS colitis and enhanced inflammation, while Tim-3 overexpression attenuated DSS colitis by decreasing the M1 macrophage response. Co-culture of Tim-3-overexpressing macrophages with intestinal lymphocytes decreased the pro-inflammatory response. Tim-3 shaped intestinal macrophage polarization may be TLR-4 dependent since Tim-3 blockade failed to exacerbate colitis or increase M1 macrophage response in the TLR-4 KO model. Finally, Tim-3 signaling inhibited phosphorylation of IRF3, a TLR-4 downstream transcriptional factor regulating macrophage polarization. A better understanding of this pathway may shed new light on colitis pathogenesis and result in a new therapeutic strategy.