Abstract
Abstract Inflammasomes are multimeric protein complexes that orchestrate into the cytoplasm to exhibit different immune outcomes in response to microbial pathogens. Lipopolysaccharides (LPS) present in Gram-negative bacteria induces non-canonical NLRP3 inflammasome activation. We have recently found that interferon regulatory factor 8 (IRF8) was not required for caspase-11–mediated NLRP3 inflammasome activation during LPS transfection. Nonetheless, the role of IRF8 in Gram-negative bacteria mediated NLRP3 inflammasome activation has been unknown. In this study, we discovered that IRF8 promotes NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) infected with Gram-negative bacteria such as E. coli and C. rodentium. Furthermore, IRF8 deficient BMDMS showed reduced caspase-11 activation and gasdermin-D cleavage. Mechanistically, IRF8-mediates the activation of IRF3 for the transcription of interferon beta—which is required for caspase-11–dependent NLRP3 inflammasome activation in the infected BMDMs. Overall, we found that IRF8 regulated interferon beta production in response to Gram-negative bacteria is a driving factor for the activation of NLRP3 inflammasome.
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