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Mechanism and targeting of inflammasome activation in lung inflammation and injury

肺部炎症和损伤中炎症小体激活的机制和靶向

基本信息

批准号：
10657193
负责人：
Gang Liu
金额：
$ 57.11万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-16 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657193
关键词：
Acute Lung Injury Apoptosis Bacterial Pneumonia CASP1 gene Cell Death Data Disease Down-Regulation Foundations Genetic Transcription IL18 gene Immune System Diseases Immune system In Vitro Infection Inflammasome Inflammatory Inflammatory Response Interleukin-1 beta Investigation Knock-out Lens development Light Lung Lymphangiogenesis Lytic Macrophage Mediating Mus Natural Immunity Pathogenesis Phagocytosis Play Process Production Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Inflammation Regulation Review Literature Role Solid System Testing Ubiquitin antimicrobial complement system cytokine in vivo insight knock-down lung injury member microbial multicatalytic endopeptidase complex novel overexpression pharmacologic response sensor therapeutic target therapeutically effective tissue injury transcription factor

项目摘要

The NLRP3 inflammasome is unique in that it requires a two-step activation process: the priming and the activating. The priming step involves the induction of NLRP3 and pro-IL-1β, whereas the activating step results in the full inflammasome activation triggered by a NLRP3 activator. Although the mechanism leading to the activation of the NLRP3 inflammasome has been increasingly clear, the regulation of this process remains poorly defined. Dysregulation of NLRP3 inflammasome has been frequently implicated in the bacterial pneumonia caused acute lung injury (ALI). MafB is a member of the large MAF transcription factor subfamily and has been implicated in immune disorders, which mainly concerns its role in macrophage apoptosis, phagocytosis and the complement system. In our preliminary studies, we made an unexpected discovery that uncovers a novel function of MafB in regulating the NLRP3 inflammasome activation. Our findings suggest that MafB is a new negative regulator of the NLRP3 inflammasome in vitro and in vivo. We hypothesize that LPS, and P. aeruginosa induced MafB downregulation is a crucial step for the NLRP3 inflammasome priming; MafB is a key player that regulates the NLRP3 inflammasome activation; MafB plays an important role in the pathogenesis of ALI; as well as targeting MafB is an effective therapeutics for ALI. We aim to comprehensively delineate the regulation of MafB expression at the transcriptional and post-translational levels during the NLRP3 inflammasome priming; to delineate the mechanism by which MafB inhibits the NLRP3 inflammasome activation; and to determine the role of MafB in LPS and P. aeruginosa induced acute lung injury (ALI).

NLRP3 炎症小体的独特之处在于它需要两步激活过程：启动和激活。启动步骤涉及 NLRP3 和 pro-IL-1β 的诱导，而激活步骤则导致由 NLRP3 激活剂触发的完全炎性体激活。尽管导致 NLRP3 炎症小体激活的机制已日益明确，但这一过程的调控仍不清楚。 NLRP3 炎性体的失调经常与细菌性肺炎引起的急性肺损伤（ALI）有关。 MafB 是 MAF 大转录因子亚家族的成员，与免疫疾病有关，主要涉及其在巨噬细胞凋亡、吞噬作用和补体系统中的作用。在我们的初步研究中，我们有了一个意想不到的发现，揭示了 MafB 在调节 NLRP3 炎症小体激活中的新功能。我们的研究结果表明，MafB 是体外和体内 NLRP3 炎症小体的新负调节因子。我们假设 LPS 和铜绿假单胞菌诱导的 MafB 下调是 NLRP3 炎症小体启动的关键步骤； MafB 是调节 NLRP3 炎症小体激活的关键角色； MafB在ALI的发病机制中发挥重要作用；以及靶向 MafB 是治疗 ALI 的有效疗法。我们的目标是全面描述 NLRP3 炎症小体启动过程中 MafB 在转录和翻译后水平的表达调控；描述 MafB 抑制 NLRP3 炎症小体激活的机制；并确定 MafB 在 LPS 和铜绿假单胞菌诱导的急性肺损伤 (ALI) 中的作用。