Mechanism and targeting of inflammasome activation in lung inflammation and injury

NLRP3炎性体的独特之处在于它需要两步激活过程：启动和激活。启动步骤包括NLRP3和pro-IL-1β的诱导，而激活步骤是由NLRP3激活剂触发的炎性体的完全激活。尽管导致NLRP3炎性小体激活的机制已经越来越清楚，但这一过程的调控仍然不明确。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。mab是MAF转录因子亚家族的一员，与免疫紊乱有关，主要涉及其在巨噬细胞凋亡、吞噬和补体系统中的作用。在我们的初步研究中，我们意外发现了mab在调节NLRP3炎性小体激活中的新功能。我们的研究结果表明，在体内和体外，mab是NLRP3炎症小体的一种新的负调节因子。我们假设LPS和P. aeruginosa诱导的mab下调是NLRP3炎性小体启动的关键步骤；MafB是调节NLRP3炎性体激活的关键参与者；MafB在ALI的发病机制中起重要作用；以及靶向mab是ALI的有效治疗方法。我们的目标是全面描述NLRP3炎症小体启动过程中转录和翻译后水平对MafB表达的调控；阐明mab抑制NLRP3炎性体激活的机制；确定mab在LPS和P. aeruginosa诱导的急性肺损伤（ALI）中的作用。

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).