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.

Immunity against fungi

“…Intestinal C. tropicalis overgrowth in Clec4d -/-mice was accompanied by a decrease in Th17 cells, impaired macrophage fungal phagocytosis, and defective intestinal epithelial cell barrier function (177). Consistent with these findings, antifungal treatment of Clec4d -/-mice reduced C. tropicalis burden and ameliorated colitis.…”

Fungal dysbiosis: immunity and interactions at mucosal barriers

“…Clec4d −/− mice developed more severe colitis, which was associated with increased C. tropicalis burden and efficiently treated with fluconazole 98 . Decreased numbers of Th17 cells, impaired phagocytosis by dectin-3-deficient macrophages and defective intestinal epithelial cell barrier in these mice can be partially responsible for C. tropicalis overgrowth.…”

“…Decreased numbers of Th17 cells, impaired phagocytosis by dectin-3-deficient macrophages and defective intestinal epithelial cell barrier in these mice can be partially responsible for C. tropicalis overgrowth. However, the mechanisms behind increased susceptibility to colitis remain unclear as several pro-inflammatory cytokines (including tumour necrosis factor) were reduced in the colons of Clec4d −/− mice 98 . Although the structure of the microbiota was not assessed in this study, augmented fungal burden and the increased relative abundance of C. tropicalis in the intestines of Clec4d −/− mice indicate changes in the fungal community.…”

The Goldilocks model of immune symbiosis with Mycobacteria and Candida colonizers

“…The superscript number(s) next to each mycobacterial PAMP indicates a corresponding reference that documents its association with or activation of TLR2 245–247 , TLR4 248 , TLR6 249 , TLR9 250 , NOD2 251 , MINCLE 252 , MARCO 253 , Dectin-2 254 , Dectin-3 255 , Mannose Receptor 256,257 , CR 258,259 , DC-SIGN 260,261 , Galectin-3 262,263 , CD36 264 , MBL 265 , Dectin-1 266 , NLRP3 267 . The superscript number(s) next to each Candida PAMP indicates a corresponding reference that documents its activation of either TLR2 268–270 , TLR4 269,270 , Dectin-1 271 , Mannose Receptor 269 , Dectin-2 272,273 , DC-SIGN 274 , Galectin-3 275 , MINCLE 276 , SCARF1 277 , CD36 277 , MBL 278 , CR3 279 , Dectin-3 280 , TLR9 281,282 , NLRP3 283 , NOD2 282 .…”