IRF8 regulated interferon beta production drives Gram-negative bacteria-mediated NLRP3 inflammasome activation

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.