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Cell. 2016 Feb 25;164(5):896-910. doi: 10.1016/j.cell.2015.12.057.

NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria.

Author information

1
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
3
Division of Gastroenterology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
4
National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
5
Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
6
Division of Gastroenterology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
7
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
8
Sanford-Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
9
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.

Abstract

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.

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PMID:
26919428
PMCID:
PMC4769378
[Available on 2017-02-25]
DOI:
10.1016/j.cell.2015.12.057
[Indexed for MEDLINE]
Free PMC Article

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