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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：
10453181
负责人：
Lin-Feng Chen
金额：
$ 7.42万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453181
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 Immune System Diseases Infection Inflammasome Inflammation Inflammatory Innate Immune Response Interleukin-1 beta Interleukin-18 Introns 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 macrophage 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.

摘要