Abstract
The human fungal microbiota known as mycobiota is increasingly recognized as a critical factor in human gut health and disease. Non-pathogenic commensal yeasts such as Saccharomyces cerevisiae promote homeostasis in the gut, whereas dysbiosis of the gut mycobiota is associated with inflammation. Glycan-binding receptors (lectins) are key host factors in host–mycobiota interaction in the gut. They are expressed on immune cells such as dendritic cells (DCs) and recognize fungal polysaccharides. This interaction is imperative to mount appropriate immune responses for immune homeostasis in the gut as well as clearance of fungal pathogens. Recent studies demonstrate that microtubule-associated protein light-chain 3 (LC3)-associated phagocytosis (LAP) is involved in lectin–fungi interactions. Yet, the biological impact of LAP on the lectin function remains largely elusive. In this report, we demonstrate that in mouse LAP is linked to dendritic cell-associated lectin 2 (Dectin-2), a C-type lectin specific to fungal α-mannan polysaccharide. We found that mouse Dectin-2 recognizes commensal yeast S. cerevisiae and Kazachstania unispora. Mouse bone marrow-derived DCs (BMDCs) produced inflammatory cytokines TNFα and IL-1β in response to the yeasts in a Dectin-2 and spleen tyrosine kinase (Syk)-dependent manner. We found that S. cerevisiae and K. unispora induced LAP in mouse BMDCs upon internalization. Furthermore, LC3 was activated by stimulation of BMDCs with the yeasts in a Dectin-2 and Syk-dependent manner. To address the biological impact of LAP on Dectin-2 yeast interaction, we established a knock-in mouse strain (Atg16L1E230, thereafter called E230), which BMDCs exhibit autophagy-active and LAP-negative phenotypes. When stimulated with yeasts, E230 BMDCs produced significantly less amounts of TNFα and IL-1β. Taken together, we revealed a novel link between Dectin-2 and LAP that enables host immune cells to respond to mycobiota.
Highlights
The human gut contains various fungal species, which form together the fungal microbiota or mycobiota
We tested Dectin-2 binding to the commensal yeast S. cerevisiae and K. unispora isolated from human feces
We found that Dectin-2 KO bone marrow-derived DCs (BMDCs) showed fewer number of yeasts associated with the cell when compared to WT BMDCs (Figure 1C)
Summary
The human gut contains various fungal species, which form together the fungal microbiota or mycobiota. The number of intestinal commensal fungi represents relatively small fraction of human microbiota when compared to bacteria; they play critical roles in gut health and disease [1]. Mycobiota dysbiosis is associated with exacerbated gut inflammation in mouse and humans [2, 3]. The most dominant fungal species are Candida albicans and Candida tropicalis in humans and mice, respectively [1, 4, 5]. Both species affect the severity of inflammatory bowel diseases. Molecular and cellular mechanisms underpinning the impact of mycobiota remain largely unknown
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