Blocking DCIR mitigates colitis and prevents colorectal tumors by enhancing the GM-CSF-STAT5 pathway

Dendritic cell immunoreceptor (DCIR; gene: Clec4a2), a member of the C-type lectin receptor family, plays important roles in homeostasis of the immune and bone systems. However, the intestinal role of this molecule is unclear. Here, we showed that the severity of dextran sodium sulfate (DSS)–induced colitis and the incidence of azoxymethane-DSS–induced intestinal tumors was reduced in Clec4a2–/– mice in an intestinal microbiota–independent manner. STAT5 phosphorylation and expression of Csf2 and tight junction genes were enhanced, while expression of Il17a and Cxcl2 was suppressed in the Clec4a2–/– mouse, which exhibited reduced infiltration of neutrophils and myeloid-derived suppressor cells. GM-CSF administration ameliorated DSS colitis associated with reduced Il17a and enhanced tight junction gene expression, whereas anti–GM-CSF significantly exacerbated the symptoms. Furthermore, blocking the ligand-DCIR interaction ameliorated colitis and prevented colorectal tumors. These observations indicate that blocking DCIR signaling ameliorate colitis and suppresses colonic tumors, suggesting DCIR as a possible target for the treatment of these diseases.