Background &amp; aims <p>Both macrophages and T cells play a critical role in inflammatory bowel disease (IBD) development. Since our previous studies have shown that a novel immune checkpoint molecule erythrocyte membrane-associated protein (ERMAP) affects macrophage polarization and negatively regulates T cell responses, we investigated the effects of ERMAP on DSS-induced colitis progression in mice.</p> Methods <p>C57BL/6 mice developed a dextran sodium sulfate (DSS) colitis model, treated with control Fc protein (Control Ig) and ERMAP-Fc fusion protein (ERMAP-Ig) for 12 days to assess colitis severity by disease activity index (DAI), weight loss, colon length, histology, flow cytometry, Q-PCR, WB, ELISA, and the effect of adoptive transfer of ERMAP knockout mice (ERMAP^-/-) peritoneal macrophages on DSS colitis mice. In vitro, the effects of the RAW264.7 macrophage cell line that interfered with ERMAP expression on macrophage polarization and T cells were analyzed by flow cytometry.</p> Results <p>We show here that administration of ERMAP protein significantly increases the proportion of anti-inflammatory M2-type macrophages and inhibits T cell activation and proliferation in DSS-induced colitis mice. Knockdown of ERMAP in RAW264.7 macrophages reduces M2-type macrophage polarization and increases T cell responses. Adoptive transfer of macrophages from ERMAP^-/- exacerbates DSS-induced colitis. Global gene expression analysis by RNA-seq shows that ERMAP inhibits the NOD-like receptor (NLR) protein family pathway in macrophages.</p> Conclusions <p>In summary, our results suggest that administration of ERMAP can protect DSS-induced colitis in mice by regulating T cell and macrophage functions. This study adds to the evidence for various mechanistic pathways associated to the pathogenesis of IBD, which could subsequently be translated to novel therapeutics.</p>