The NLRP3 Inflammasome Works as a Sensor for Detecting Hypoactivity of the Mitochondrial Src Family Kinases

J Immunol. 2023 Mar 15;210(6):795-806. doi: 10.4049/jimmunol.2200611.


Gefitinib (GF), the tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor, initiates lung inflammation through the NLR family pyrin domain containing 3 (NLRP3) inflammasome. However, the molecular targets and mechanisms underlying the inflammatory action of GF remain unknown. In this study, we identified mitochondrial Src family kinases (mSFKs) as key determinants of GF-induced NLRP3 inflammasome activation. Comprehensive analysis of the TKIs revealed that all TKIs we tested act as potent agonists for the NLRP3 inflammasome in human monocytic THP-1 cells and bone marrow-derived macrophages. Moreover, these TKIs share a common off-target activity against the mSFKs, such as c-Src, Fgr, and Fyn. Interestingly, loss of each kinase spontaneously stimulated the NLRP3 inflammasome activation in THP-1 cells. These results together suggest that NLRP3 senses hypoactivity of the mSFKs that is responsible for mitochondrial dysfunction. Thus, our findings demonstrate a mechanistic link between the NLRP3 inflammasome and mSFKs, which, to our knowledge, provides insights into a novel molecular basis and cellular function of the NLRP3 inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Humans
  • Inflammasomes* / metabolism
  • Mitochondria / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • src-Family Kinases


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • src-Family Kinases