Transcriptional Regulation of NLRC4 Inflammasome Activation

摘要 NLRC4炎性小体激活及随后Caspase-1介导的IL-1β和IL-18成熟 和下垂对于防止沙门氏菌等细菌病原体的感染至关重要 鼠伤寒沙门氏菌(S.typhimurium)虽然关于NLRC4炎症体是如何被激活的已知很多 通过NAIPS感测鞭毛蛋白和III型分泌系统(T3SS)的成分，人们对鞭毛蛋白和T3SS如何 NLRC4炎症体激活受到调控。表观遗传因子Brd4在先天免疫中的关键作用 通过调节巨噬细胞中炎症基因的表达进行反应。BRD4通过以下方式刺激基因表达 与不同转录因子在启动子或增强子上的选择性结合。我们最近的研究 证明具有髓系特异性Brd4缺失的小鼠对鼠伤寒沙门氏菌更敏感 感染后巨噬细胞caspase-1活性和IL-1β成熟降低。更重要的是， Brd4缺陷小鼠巨噬细胞和Brd4中NAIPS和NLRC4转录下调 抑制人巨噬细胞。这些令人兴奋的结果表明，Brd4可能调节了 NLRC4炎症体通过控制NAIPS和NLRC4的转录，NLRC4是炎症的两个主要成分 NLRC4炎症体。事实上，我们最新的研究表明，Brd4与 IRF8/PU.1并与NAIPS启动子上的IRF8和PU.1结合基序结合以维持 NAIPS在巨噬细胞中的表达。然而，Brd4如何调控NLRC4的表达在很大程度上仍然存在 未知。在这个R03提案中，我们将研究Brd4介导的NLRC4的转录调控 表达和NLRC4炎性小体激活。拟议研究的完成将提供新的见解 研究NLRC4炎症体的转录调控，为肿瘤的治疗提供新的途径 靶向Brd4的NLRC4炎症体介导的细菌感染和免疫疾病。

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.