NF-kappa B Restricts Inflammasome Activation via Elimination of Damaged Mitochondria

摘要

Nuclear factor kappa B (NF-kappa B), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1 beta and NLRP3 expression. NF-kappa B, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-kappa B exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptorp62/SQSTM1. ExternalNLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1-and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, includingmtDNAandmtROS. 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-1 beta-dependent inflammation, enhancing macrophage death. Therefore, the "NF-kappa B-p62-mitophagy" pathway is a macrophage-intrinsic regulatory loop through which NF-kappa B restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair.