MafB regulates NLRP3 inflammasome activation by sustaining p62 expression in macrophages.
MafB regulates NLRP3 inflammasome activation by sustaining p62 expression in macrophages.
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DOI：
10.1038/s42003-023-05426-5
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发表时间：
2023-10-16
影响因子：
5.9
通讯作者：
Liu, Gang
中科院分区：
文献类型：
--
作者：
Cui, Huachun;Banerjee, Sami;Xie, Na;Dey, Tapan;Liu, Rui-Ming;Sanders, Yan Y.;Liu, Gang
NLRP3炎症体的激活是一个两步过程：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。尽管NLRP3炎性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完全清楚。在这项研究中，我们发现内毒素和铜绿假单胞菌引起巨噬细胞MafB转录的快速下调，导致MafB蛋白水平的快速下降，因为MafB是短暂的，并不断被泛素/蛋白酶体系统降解。我们发现，MafB基因敲除或敲除显著增强了巨噬细胞中NLRP3，但不能增强NLRP1，NLRC4，或AIM2，炎症体的激活。相反，MafB的药理诱导降低了NLRP3炎症体的激活。从机制上讲，我们发现MafB支持p62的表达，p62是自噬/有丝分裂吞噬的关键调节因子。我们发现MafB抑制线粒体损伤，抑制线粒体ROS的产生和DNA胞质的释放。此外，我们发现髓系MafB缺陷小鼠在体内表现出对脂多糖治疗和铜绿假单胞菌感染以及肺内铜绿假单胞菌清除不足的反应，系统和肺组织中IL-1β的产生增加。综上所述，我们的研究表明MafB是NLRP3炎症体的重要负调控因子。我们的发现表明，提高MafB的策略可能有效地治疗由于NLRP3炎症小体过度激活而引起的免疫紊乱。巨噬细胞中NLRP3炎症体的最大激活依赖于蛋白酶体介导的MafB在启动阶段的快速降解。
Activation of the NLRP3 inflammasome is a two-step process: the priming and the activating. The priming step involves the induction of NLRP3 and pro-IL-1β, while the activating step leads to the full inflammasome activation triggered by a NLRP3 activator. Although mechanisms underlying the NLRP3 inflammasome activation have been increasingly clear, the regulation of this process remains incompletely understood. In this study, we find that LPS and Pseudomonas aeruginosa cause a rapid downregulation in MafB transcription in macrophages, which leads to a quick decline in the level of MafB protein because MafB is short-lived and constantly degraded by the ubiquitin/proteasome system. We find that MafB knockdown or knockout markedly enhances the NLRP3, but not the NLRP1, NLRC4, or AIM2, inflammasome activation in macrophages. Conversely, pharmacological induction of MafB diminishes the NLRP3 inflammasome activation. Mechanistically, we find that MafB sustains the expression of p62, a key mediator of autophagy/mitophagy. We find that MafB inhibits mitochondrial damage, and mitochondrial ROS production and DNA cytoplasmic release. Furthermore, we find that myeloid MafB deficient mice demonstrate increased systemic and lung IL-1β production in response to LPS treatment and P. aeruginosa infection and deficient lung P. aeruginosa clearance in vivo. In conclusion, our study demonstrates that MafB is an important negative regulator of the NLRP3 inflammasome. Our findings suggest that strategies elevating MafB may be effective to treat immune disorders due to excessive activation of the NLRP3 inflammasome. Maximum activation of the NLRP3 inflammasome in macrophages is dependent on rapid proteasome-mediated degradation of MafB during the priming stage.
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DOI：
10.4049/jimmunol.1202496
发表时间：
2013-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Banerjee S;Xie N;Cui H;Tan Z;Yang S;Icyuz M;Abraham E;Liu G
通讯作者：
Liu G
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
13.3
作者：
Kim, Min-Ji;Bae, Soo Han;Yoon, Joo-Heon
通讯作者：
Yoon, Joo-Heon
在细胞死亡和炎症的串扰中进行了编程坏死。
影响因子：
29.7
作者：
Chan FK;Luz NF;Moriwaki K
通讯作者：
Moriwaki K
影响因子：
20.3
作者：
Kim, Kabsun;Kim, Jung Ha;Kim, Nacksung
通讯作者：
Kim, Nacksung