NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / metabolism
  • Macrophages / metabolism
  • Mice
  • Mitochondria / metabolism*
  • NF-kappa B p50 Subunit / metabolism*
  • Reactive Oxygen Species / metabolism
  • Sequestosome-1 Protein
  • Ubiquitin-Protein Ligases / metabolism


  • Adaptor Proteins, Signal Transducing
  • Heat-Shock Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NF-kappa B p50 Subunit
  • Reactive Oxygen Species
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Nfkb1 protein, mouse
  • Ubiquitin-Protein Ligases
  • parkin protein