SYK-CARD9 Signaling Axis Promotes Gut Fungi-Mediated Inflammasome Activation to Restrict Colitis and Colon Cancer

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SUMMARYFungi represent a significant proportion of the gut microbiota. Aberrant immune responses to fungi are frequently observed in inflammatory bowel diseases (IBD) and colorectal cancer (CRC), and mutations in the fungal-sensing pathways are associated with the pathogenesis of IBD. Fungal recognition receptors trigger downstream signaling via the common adaptor protein CARD9 and the kinase SYK. Here we found that commensal gut fungi promoted inflammasome activation during AOM-DSS-induced colitis. Myeloid cell-specific deletion of Card9 or Syk reduced inflammasome activation and interleukin (IL)-18 maturation and increased susceptibility to colitis and CRC. IL-18 promoted epithelial barrier restitution and interferon-γ production by intestinal CD8+ T cells. Supplementation of IL-18 or transfer of wild-type myeloid cells reduced tumor burden in AOM-DSS-treated Card9−/− and Sykfl/flLysMCre/+ mice, whereas treatment with anti-fungal agents exacerbated colitis and CRC. CARD9 deletion changes the gut microbial landscape, suggesting that SYK-CARD9 signaling maintains a microbial ecology that promotes inflammasome activation and thereby restrains colitis and colon tumorigenesis.Graphical AbstractHIGHLIGHTSCommensal gut fungi contribute to inflammasome activation during experimental colitisMicrobial landscape is altered in Card9−/− miceDefective inflammasome activation, IL-18 maturation in myeloid cells lacking CARD9 or SYKMetronidazole treatment protects Card9−/− and SykLysM mice from colon tumorigenesisFungi represent a significant proportion of the gut microbiota, but how anti-fungal immunity contributes to tumor-promoting inflammatory responses is unclear. Malik et al. find that recognition of commensal gut fungi, sensed via the Card9-Syk signaling axis, is protective in the context of inflammation-associated cancer. IL-18 maturation downstream of inflammasome activation promotes epithelial barrier restitution and IFN-γ production by intestinal CD8+ T cells.

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