Journal
CELL
Volume 164, Issue 5, Pages 896-910Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.12.057
Keywords
-
Categories
Funding
- Cancer Research Institute (CRI) Irvington postdoctoral fellowship
- JSPS KAKENHI [15H06547]
- Kanae Foundation for the Promotion of Medical Science
- Rotary Foundation
- Sara Borrell fellowship under ISCIII/MICINN program
- CRI-Irvington
- German Research Foundation [SH721/1-1]
- Canadian Institutes of Health Research [MFE-135425]
- NIH [AI043477, CA163798, GM103412, AA020172, DK085252, ES010337, HL087023, AI52430, CA192642, CA030199, CA132847, CA172025]
- Leukemia and Lymphoma Society SCOR [20132569]
- Alliance for Lupus Research [257214]
- Grants-in-Aid for Scientific Research [15H06547] Funding Source: KAKEN
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available