Mincle/Syk signaling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis in Crohn's disease.

BACKGROUND: Macrophage-inducible C-type lectin (Mincle) signaling plays a proinflammatory role in different organs such as the brain and liver, but its role in intestinal inflammation including Crohn's Disease (CD) remains unknown. METHODS: The characteristics of Mincle signaling expression in CD patients and experimental colitis were examined. The functional role of Mincle signaling in the intestine was addressed in experimental colitis models in vivo by using Mincle knock out (Mincle-/-) mice. In addition, neutralising anti-Mincle antibody, downstream spleen tyrosine kinase (Syk) inhibitor and Mincle pharmacologic agonist were used to study the Mincle signaling in intestine. Bone marrow-derived macrophages were collected from mice and used to further verify the effect of Mincle signaling in macrophages. RESULTS: This study has shown that Mincle signaling was significantly elevated in active human CD and experimental colitis, and macrophages were the principal leukocyte subset that up-regulate Mincle signaling. Mincle deficiency and Syk pharmacologic inhibition ameliorated the colitis by reducing induced macrophage pyroptosis, and activation of Mincle with the agonist aggravate the intestinal inflammation. The ex vivo studies demonstrated that activation of Mincle signaling promoted the release of proinflammatory cytokines while its absence restricted release of proinflammatory cytokines from pyroptosis of macrophage. In addition, Mincle/Syk signaling in macrophage could promote the production of chemokines to recruit neutrophils by activating Mitogen-Activated Protein Kinase (MAPK) during intestinal inflammation. CONCLUSION: Mincle signaling promotes intestinal mucosal inflammation by inducing macrophage pyroptosis. Modulation of the Mincle/Syk axis emerges as a potential therapeutic strategy to target inflammation and treat CD.