ERMAP attenuates DSS-induced colitis in mice by regulating macrophage and T cell functions.

BACKGROUND & AIMS: 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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.