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Dectin-3 Deficiency Promotes Colitis Development due to Impaired Antifungal Innate Immune Responses in the Gut
Tingting Wang1,2, Deng Pan1,3, Zhicheng Zhou1,3
1Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
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.
Insights
Mice lacking Dectin-3 showed increased susceptibility to colitis and Candida tropicalis overgrowth. Restoring Dectin-3 function or using antifungal therapy improved gut homeostasis and colitis symptoms.
Area of Science:
- Immunology
- Microbiology
- Gastroenterology
Background:
- Gut commensal fungi interact with the immune system to maintain intestinal homeostasis.
- Dectin-3 is a C-type lectin receptor crucial for sensing fungal infections.
Purpose of the Study:
- To investigate the role of Dectin-3 in the context of gut fungalCommensalism and inflammatory bowel disease.
- To elucidate the mechanisms by which Dectin-3 influences the gut immune response to Candida tropicalis.
Main Methods:
- Dextran sodium sulfate (DSS)-induced colitis model in wild-type and Dectin-3-deficient (Clec4d-/-) mice.
- Assessment of fungal burden, immune cell function (macrophages), and epithelial cell repair.
- Evaluation of therapeutic interventions including antifungal therapy.
Main Results:
- Dectin-3 deficiency exacerbated DSS-induced colitis and increased Candida tropicalis burden.
- Dectin-3 deficiency impaired macrophage phagocytosis, fungicidal activity, and inflammatory signaling.
- Dectin-3-deficient macrophages exhibited reduced capacity to promote colonic epithelial cell repair.
- Antifungal therapy ameliorated colitis in Dectin-3-deficient mice.
Conclusions:
- Dectin-3 plays a critical role in maintaining colonic homeostasis by regulating the immune response to commensal fungi like Candida tropicalis.
- Dectin-3 deficiency compromises innate immune defenses, leading to increased susceptibility to colitis.
- Targeting fungalCommensalism presents a potential therapeutic strategy for managing colitis.
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