An inhibitory receptor leukocyte mono-immunoglobulin-like receptor 3/CD300f deficiency aggravates DSS-induced colitis (MUC8P.737)

Abstract

Abstract Leukocyte mono-immunoglobulin-like receptor 3 (LMIR3) (also called CD300f) is an inhibitory receptor. LMIR3 is mainly expressed in myeloid cells, including mast cells. The binding of LMIR3 to its ligand ceramide inhibits IgE- and mast cell-dependent allergic responses. It was recently reported that ATP-induced activation of mast cells via P2X7 purinoceptor contributes to the initiation and progression of intestinal inflammation. Here we show that LMIR3 is a negative regulator of dextran sodium sulfate (DSS)-induced colitis, a murine model of ulcerative colitis (UC). Notably, Lmir3-/- mice were highly susceptible to DSS-induced colitis. We found a prominent increase in inflammatory cells, including degranulated mast cells, in the colonic lamina propria of DSS-treated Lmir3-/- mice. Mast cell-deficient KitWsh/Wsh mice engrafted with LMIR3 deficient bone-marrow-derived mast cells (BMMCs) exhibited increased susceptibility to DSS-induced colitis as compared with those with wild-type (WT) BMMCs. Importantly, ceramide-LMIR3 binding suppressed activation of ATP-stimulated BMMCs. Consistently, treatment with ceramide liposomes improved DSS-induced colitis in WT mice, but not in Lmir3-/- mice. Taken together, these results indicated that LMIR3 negatively regulated DSS-induced colitis by inhibiting ATP-mediated mast cell activation through ceramide-LMIR3 binding. Accordingly, LMIR3-targeted ceramide liposomes would provide novel therapeutic strategies for UC.