Mechanism and targeting of inflammasome activation in lung inflammation and injury

NLRP3炎症体的独特之处在于它需要一个两步激活过程：启动和激活。启动步骤包括诱导NLRP3和前IL-1β，而激活步骤导致由NLRP3激活剂触发的完全炎症小体激活。虽然导致NLRP3炎症小体激活的机制已经越来越清楚，但对这一过程的调控仍不清楚。细菌性肺炎引起的急性肺损伤(ALI)往往与NLRP3炎症小体的调节失调有关。MafB是MAF转录因子家族中的一员，与免疫紊乱有关，主要涉及巨噬细胞的凋亡、吞噬和补体系统。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炎症体激活方面的一个新功能。我们的研究结果表明，MafB在体外和体内都是一种新的NLRP3炎症体的负调控因子。我们推测，内毒素和铜绿假单胞菌诱导的MafB下调是NLRP3炎性小体启动的关键步骤；MafB是调节NLRP3炎性小体激活的关键分子；MafB在ALI的发病机制中起重要作用；靶向MafB是治疗ALI的有效方法。本研究旨在全面了解MafB在NLRP3炎症小体启动过程中转录和翻译后水平的表达调控，阐明MafB抑制NLRP3炎症小体激活的机制，并探讨MafB在内毒素和铜绿假单胞菌诱导的急性肺损伤(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).