Transcriptional Regulation of NLRC4 Inflammasome Activation

NLRC4 炎症小体激活的转录调控

基本信息

批准号：
10560610
负责人：
Lin-Feng Chen
金额：
$ 7.41万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-02 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560610
关键词：
Apoptosis Bacterial Infections Binding Bone Marrow Bromodomain CASP1 gene Cell Death Cell Nucleus ChIP-seq Complex Data Disease Enhancers Epigenetic Process Family Family member Flagellin Gene Expression Genes Genetic Transcription Host Defense Human IL18 gene Immune System Diseases Infection Inflammasome Inflammation Inflammatory Innate Immune Response Interleukin-1 beta Introns Macrophage Malignant Neoplasms Mediating Molecular Multiprotein Complexes Mus Myelogenous Natural Immunity Needles Nucleotides Pattern Play Production Proteins Reader Regulation Regulator Genes Rod Role Salmonella infections Salmonella typhimurium Stimulus Structure Transcriptional Regulation Type III Secretion System Pathway cytokine enteric pathogen insight marenostrin novel therapeutic intervention pathogen pathogenic bacteria promoter recruit response selective expression sensor transcription factor

项目摘要

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.

抽象的 NLRC4 炎症小体激活以及随后的 caspase-1 介导的 IL-1β 和 IL-18 成熟细胞焦亡对于防止沙门氏菌等细菌病原体感染至关重要鼠伤寒沙门氏菌 (S. Typhimurium) 是如何激活 NLRC4 炎性小体的？ Naips 感测鞭毛蛋白和 III 型分泌系统 (T3SS) 的成分，但人们对如何 NLRC4 炎症小体激活受到调节，表观遗传因子 Brd4 在先天免疫中发挥着关键作用。 Brd4 通过调节巨噬细胞中的炎症基因表达来刺激基因表达。我们最近的研究与启动子或增强子上的不同转录因子选择性关联。证明骨髓谱系特异性删除 Brd4 的小鼠对鼠伤寒沙门氏菌更敏感更重要的是，感染会导致巨噬细胞中 caspase-1 活化和 IL-1β 成熟减少。 Naips 和 NLRC4 的转录在 Brd4 缺陷型小鼠巨噬细胞和 Brd4 中下调这些令人兴奋的结果表明 Brd4 可能调节巨噬细胞的激活。 NLRC4 炎症小体通过控制 Naips 和 NLRC4（炎症小体的两个主要成分）的转录事实上，我们最近的研究表明 Brd4 与 NLRC4 形成了复合物。 IRF8/PU.1 并与 Naips 启动子上的 IRF8 和 PU.1 结合基序结合，以维持然而，Brd4 如何调节 NLRC4 的表达在很大程度上仍然存在。在这个 R03 提案中，我们将研究 Brd4 介导的 NLRC4 转录调控。表达和 NLRC4 炎症小体激活的研究的完成将提供新的见解。 NLRC4炎症小体的转录调控，为治疗提供新的途径通过靶向 Brd4 NLRC4 炎症小体介导的细菌感染和免疫疾病。