Transcriptional Regulation of NLRC4 Inflammasome Activation

摘要 NLRC 4炎性小体激活和随后caspase-1介导的IL-1β和IL-18成熟 和焦亡对于保护免受细菌病原体如沙门氏菌的感染至关重要 鼠伤寒沙门氏菌（S.鼠伤寒沙门氏菌）。虽然关于NLRC 4炎性体如何被激活的了解很多， 尽管Naips在感受鞭毛蛋白和III型分泌系统（T3 SS）组分方面的研究进展缓慢，但关于鞭毛蛋白和T3 SS组分如何作用的研究却知之甚少。 NLRC 4炎性小体活化受到调节。表观遗传因子Brd 4在先天免疫中起关键作用 通过调节巨噬细胞中的炎症基因表达来应答。Brd 4刺激基因表达， 与启动子或增强子上的不同转录因子的选择性缔合。我们最近的研究 表明骨髓谱系特异性缺失Brd 4的小鼠对S.鼠伤寒 巨噬细胞中caspase-1活化和IL-1β成熟减少。更重要的是， Naips和NLRC 4的转录在Brd 4缺陷小鼠巨噬细胞中下调，Brd 4缺陷小鼠巨噬细胞中Naips和NLRC 4的转录在Brd 4缺陷小鼠巨噬细胞中下调。 抑制人类巨噬细胞。这些令人兴奋的结果表明Brd 4可能调节 NLRC 4炎性体通过控制Naips和NLRC 4的转录，Naips和NLRC 4是炎症的两个主要成分。 NLRC 4炎性小体。事实上，我们最近的研究表明，Brd 4形成了一个复合物， IRF 8/PU. 1，并与Naips启动子上的IRF 8和PU. 1结合基序结合，以维持Naips启动子上的IRF 8/PU. Naips在巨噬细胞中的表达。然而，Brd 4如何调节NLRC 4的表达在很大程度上仍然是未知的。 未知在这个R 03的建议中，我们将研究Brd 4介导的NLRC 4的转录调控， 表达和NLRC 4炎性体活化。完成拟议的研究将提供新的见解 研究NLRC 4炎性小体的转录调控，为肿瘤的治疗提供新的途径。 NLRC 4炎性小体介导的细菌感染和免疫疾病通过靶向Brd 4。

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.