| First Author | Zhong Z | Year | 2016 |
| Journal | Cell | Volume | 164 |
| Issue | 5 | Pages | 896-910 |
| PubMed ID | 26919428 | Mgi Jnum | J:230797 |
| Mgi Id | MGI:5766077 | Doi | 10.1016/j.cell.2015.12.057 |
| Citation | Zhong Z, et al. (2016) NF-kappaB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164(5):896-910 |
| abstractText | Nuclear factor kappaB (NF-kappaB), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1beta and NLRP3 expression. NF-kappaB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-kappaB 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-1beta-dependent inflammation, enhancing macrophage death. Therefore, the "NF-kappaB-p62-mitophagy" pathway is a macrophage-intrinsic regulatory loop through which NF-kappaB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair. |
