NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria.
NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria.
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NF-κB通过清除受损的线粒体抑制炎性体活化。
DOI：
10.1016/j.cell.2015.12.057
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发表时间：
2016-02-25
期刊：
影响因子：
64.5
通讯作者：
Karin M
中科院分区：
文献类型：
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作者：
Zhong Z;Umemura A;Sanchez-Lopez E;Liang S;Shalapour S;Wong J;He F;Boassa D;Perkins G;Ali SR;McGeough MD;Ellisman MH;Seki E;Gustafsson AB;Hoffman HM;Diaz-Meco MT;Moscat J;Karin M
NF-κB是炎症的关键活化剂，通过诱导pro-IL-1β和NLRP 3表达来启动NLRP 3-炎性体活化。然而，NF-κB也通过不明确的机制防止过度炎症并抑制NLRP 3-炎性体活化。我们现在发现NF-κB通过诱导自噬受体p62/SQSTM 1的延迟积累发挥其抗炎活性。外部NLRP 3激活刺激触发一种形式的线粒体（mt）损伤，这种损伤是半胱天冬酶-1和NLRP 3独立的，并导致直接NLRP 3炎性体激活剂（包括mtDNA和mtROS）的释放。受损的线粒体经历帕金森依赖性泛素缀合，并被p62特异性识别，这诱导其线粒体吞噬清除。巨噬细胞特异性p62消融导致受损线粒体的显著积累和过度的IL-1β依赖性炎症，从而增强巨噬细胞死亡。因此，“NF-κB-p62-线粒体自噬”途径是一种巨噬细胞内源性调节环，NF-κB通过该途径抑制其自身的促炎活性，并协调维持体内平衡并有利于组织修复的自限性宿主反应。
NF-κB, a key activator of inflammation primes the NLRP3-inflammasome for activation by inducing pro-IL-1β and NLRP3 expression. NF-κB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-κB exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptor p62/SQSTM1. External NLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1- and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, including mtDNA and mtROS. Damaged mitochondria undergo Parkin-dependent ubiquitin conjugation and are specifically recognized by p62, which induces their mitophagic clearance. Macrophage-specific p62 ablation causes pronounced accumulation of damaged mitochondria and excessive IL-1β-dependent inflammation, enhancing macrophage death. Therefore, the “NF-κB-p62-mitophagy” pathway is a macrophage-intrinsic regulatory loop through which NF-κB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair.