In the inflamed intestine, triggering receptor expressed on myeloid cells-1 (TREM-1) is highly expressed by macrophages, contributing to the pathogenesis of inflammatory bowel disease (IBD) by augmenting pro-inflammatory responses. Surprisingly, our data showed that TREM-1 deficiency (TREM-1 KO) does not protect mice against dextran sodium sulfate (DSS)-induced colitis, instead, increases the mortality due to the impaired intestinal epithelium barrier functions. Further investigation showed lacking TREM-1 loss the capability to activate group 3 innate lymphoid cells (ILC3s) in inflamed colons. TREM-1 mediates inflammatory macrophage polarization results in enhancing inflammatory cytokines production, particularly IL-1β, and furthermore modulates interleukin-22 (IL-22) production by ILCs both in vitro and in vivo. Accordingly, the DSS-mediated intestinal tissue damage is ameliorated by supplying IL-22 in TREM-1 KO mice. Here we address a novel protective role of TREM-1 in promoting IL-22 production by ILCs through modulating inflammatory macrophages polarization during DSS-induced acute colitis.