Dectin-3 Deficiency Promotes Colitis Development due to Impaired Antifungal Innate Immune Responses in the Gut

Abstract

Interactions between commensal fungi and gut immune system are critical for establishing colonic homeostasis. Here we found that mice deficient in Dectin-3 ( Clec4d ^-/- ), a C-type lectin receptor that senses fungal infection, were more susceptible to dextran sodium sulfate (DSS)-induced colitis compared with wild-type mice. The specific fungal burden of Candida ( C.) tropicalis was markedly increased in the gut after DSS treatment in Clec4d ^-/- mice, and supplementation with C. tropicalis aggravated colitis only in Clec4d ^-/- mice, but not in wild-type controls. Mechanistically, Dectin-3 deficiency impairs phagocytic and fungicidal abilities of macrophages, and C. tropicalis-induced NF-κB activation and cytokine production. The conditioned media derived from Dectin-3-deficient macrophages were defective in promoting tissue repairing in colonic epithelial cells. Finally, anti-fungal therapy was effective in treating colitis in Clec4d ^-/- mice. These studies identified the role of Dectin-3 and its functional interaction with commensal fungi in intestinal immune system and regulation of colonic homeostasis.

Author Summary

C-type lectin receptors (CLRs) comprise a diverse family of soluble and trans-membrane proteins that function as pattern recognition receptors (PRRs). Dectin-3 (also known as MCL/CLECSF8/Clec4d), a myeloid cell-specific CLR family member, could recognize bacterial and fungal components and induce intracellular signaling pathways that regulate the immune response. Although investigators have explored the role of Dectin-3 in systemic immunity, its function in the gastrointestinal immune system is not clear. Using a dextran sodium sulfate (DSS)-induced colitis mice model, we show here Dectin-3-deficient mice were more susceptible to DSS-induced colitis compared with wild-type mice. The specific fungal burden of a commensal fungi C. tropicalis was markedly increased in the gut after DSS treatment in Dectin-3-deficient mice, and antifungal therapy could effectively protect these mice from colitis. Taken together, we demonstrate the important function of Dectin-3 and its functional interaction with commensal fungi in intestinal immune responses and regulation of colonic homeostasis.