K + Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria

Immunity. 2016 Oct 18;45(4):761-773. doi: 10.1016/j.immuni.2016.08.010. Epub 2016 Sep 27.

Abstract

Imiquimod is a small-molecule ligand of Toll-like receptor-7 (TLR7) that is licensed for the treatment of viral infections and cancers of the skin. Imiquimod has TLR7-independent activities that are mechanistically unexplained, including NLRP3 inflammasome activation in myeloid cells and apoptosis induction in cancer cells. We investigated the mechanism of inflammasome activation by imiquimod and the related molecule CL097 and determined that K+ efflux was dispensable for NLRP3 activation by these compounds. Imiquimod and CL097 inhibited the quinone oxidoreductases NQO2 and mitochondrial Complex I. This induced a burst of reactive oxygen species (ROS) and thiol oxidation, and led to NLRP3 activation via NEK7, a recently identified component of this inflammasome. Metabolic consequences of Complex I inhibition and endolysosomal effects of imiquimod might also contribute to NLRP3 activation. Our results reveal a K+ efflux-independent mechanism for NLRP3 activation and identify targets of imiquimod that might be clinically relevant.

MeSH terms

  • Animals
  • Electron Transport Complex I / metabolism
  • Inflammasomes / metabolism*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism*
  • NIMA-Related Kinases / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Potassium / metabolism*
  • Quinone Reductases / metabolism
  • RNA, Small Nuclear / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Toll-Like Receptor 7 / metabolism

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA, Small Nuclear
  • Reactive Oxygen Species
  • Toll-Like Receptor 7
  • NRH - quinone oxidoreductase2
  • Quinone Reductases
  • NIMA-Related Kinases
  • Electron Transport Complex I
  • Potassium