Card9 Mediates Intestinal Epithelial Cell Restitution, T-helper 17 Responses, and Control of Bacterial Infection in Mice.

International audienceBACKGROUND & AIMS: Caspase recruitment domain 9 (CARD9) is an adaptor protein that integrates signals downstream of pattern recognition receptors. CARD9 has been associated with auto-inflammatory disorders, and loss-of-function mutations have been associated with chronic mucocutaneous candidiasis, but the role of CARD9 in intestinal inflammation is unknown. We characterized the role of Card9 in mucosal immune responses to intestinal epithelial injury and infection. METHODS: We induced intestinal inflammation in Card9-null mice by administration of dextran sulfate sodium (DSS) or Citrobacter rodentium. We analyzed body weight, assessed inflammation by histology, and measured levels of cytokines and chemokines using quantitative reverse transcription-PCR and ELISAs. Cell populations were compared between wild-type and Card9-null mice by flow cytometry analysis. RESULTS: Colon tissues and mesenteric lymph nodes of Card9-null mice had reduced levels of interleukin (IL)-6, interferonγ, and T-helper (Th)17 cytokines following administration of DSS, compared to wild-type mice. IL-17A and IL-22 expression were reduced in the recovery phase following DSS administration, coincident with decreased expression of anti-microbial peptides and the chemokine Ccl20. Although Card9-null mice had more intestinal fungi based on 18S analysis, their Th17 responses remained defective even when an anti-fungal agent was administered throughout DSS exposure. Moreover, Card9-null mice had impaired immune responses to Citrobacter rodentium, characterized by decreased levels of colonic IL-6, IL-17A, IL-22, and RegIIIγ, as well as fewer IL-22-producing innate lymphoid cells in colon lamina propria. CONCLUSIONS: The adaptor protein CARD9 coordinates Th17- and ILC-mediated intestinal immune responses following epithelial injury in mice