Transcriptional Regulation of NLRC4 Inflammasome Activation

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ABSTRACT The NLRC4 inflammasome activation and the subsequent caspase-1-mediated maturation of IL-1β and IL-18 and pyroptosis are critical for protection against infection by bacterial pathogens such as Salmonella Typhimurium (S. Typhimurium). While much is known about how NLRC4 inflammasome is activated by sensing flagellin and components of type III secretion system (T3SS) by Naips, little is known about how the NLRC4 inflammasome activation is regulated. Epigenetic factor Brd4 plays a critical role in innate immune response by regulating inflammatory gene expression in macrophages. Brd4 stimulates gene expression by selective association with different transcription factors on promoters or enhancers. Our recent study demonstrate that mice with myeloid lineage-specific deletion of Brd4 were more sensitive to S. Typhimurium infection with reduced caspase-1 activation and IL-1β maturation in macrophages. More importantly, transcription of Naips and NLRC4 was down-regulated in Brd4-deficient mouse macrophages and Brd4 inhibited human macrophages. These exciting results suggest that Brd4 might modulate the activation of NLRC4 inflammasome by controlling the transcription of Naips and NLRC4, the two major components of NLRC4 inflammasome. Indeed, our most recent study demonstrate that Brd4 formed a complex with IRF8/PU.1 and bound to the IRF8 and PU.1 binding motifs on the promoters of Naips to maintain the expression of Naips in macrophages. However, how Brd4 regulates the expression of NLRC4 remains largely unknown. In this R03 proposal, we will investigate Brd4-mediated transcriptional regulation of NLRC4 expression and NLRC4 inflammasome activation. Completion of the proposed studies will provide new insights into the transcriptional regulation of NLRC4 inflammasome and provide new therapeutic approaches for NLRC4 inflammasome-mediated bacterial infection and immune disease by targeting Brd4.