CARD9+ Microglia Orchestrate Antifungal Immunity via IL-1β and CXCL1-mediated Neutrophil Recruitment
Research output: Contribution to journal › Article
Colleges, School and Institutes
The C-type lectin receptor/Syk adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human CARD9-deficiency causes fungal-specific CNS-targeted infection susceptibility. CARD9 is required for neutrophil recruitment to the fungal-infected CNS, which mediates fungal clearance. Here, we investigated host and pathogen factors that promote protective neutrophil recruitment during Candida albicans CNS invasion. IL-1β was essential for CNS antifungal immunity by driving CXCL1 production, which recruited CXCR2-expressing neutrophils. Neutrophil-recruiting IL-1β and CXCL1 production was induced in microglia by the fungal-secreted toxin Candidalysin, in a p38-cFos-dependent manner. Importantly, microglia relied on CARD9 for production of IL-1β, via both Il1b transcriptional regulation and inflammasome activation, and of CXCL1 in the fungal-infected CNS. Microglia-specific Card9 deletion impaired IL-1β and CXCL1 production and neutrophil recruitment, and increased CNS fungal proliferation. Taken together, an intricate network of host-pathogen interactions promotes CNS antifungal immunity, which is impaired in human CARD9-deficiency leading to CNS fungal disease.
|Number of pages||12|
|Early online date||17 Apr 2019|
|Publication status||Published - May 2019|