NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria

Zhenyu Zhong, Atsushi Umemura, Elsa Sanchez-Lopez, Shuang Liang, Shabnam Shalapour, Jerry Wong, Feng He, Daniela Boassa, Guy Perkins, Syed Raza Ali, Matthew D. McGeough, Mark H. Ellisman, Ekihiro Seki, Asa B. Gustafsson, Hal M. Hoffman, Maria T. Diaz-Meco, Jorge Moscat, Michael Karin

Research output: Contribution to journalArticle

337 Scopus citations

Abstract

Summary Nuclear factor κB (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.

Original languageEnglish (US)
Pages (from-to)896-910
Number of pages15
JournalCell
Volume164
Issue number5
DOIs
StatePublished - Feb 25 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhong, Z., Umemura, A., Sanchez-Lopez, E., Liang, S., Shalapour, S., Wong, J., He, F., Boassa, D., Perkins, G., Ali, S. R., McGeough, M. D., Ellisman, M. H., Seki, E., Gustafsson, A. B., Hoffman, H. M., Diaz-Meco, M. T., Moscat, J., & Karin, M. (2016). NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell, 164(5), 896-910. https://doi.org/10.1016/j.cell.2015.12.057