The second-generation tyrosine kinase inhibitor afatinib inhibits IL-1β secretion via blocking assembly of NLRP3 inflammasome independent of epidermal growth factor receptor signaling in macrophage

Mol Immunol. 2023 Jan:153:135-145. doi: 10.1016/j.molimm.2022.11.009. Epub 2022 Dec 7.

Abstract

Chronic inflammation might lead to many malignancies, and inadequate resolution could play a crucial role in tumor invasion, progression and metastases. Afatinib is a second-generation tyrosine kinase inhibitor targeting epidermal growth factor receptor in non-small cell lung cancer. Few studies showed the correlation of afatinib and the innate immune system especially macrophage. Our study showed that afatinib could block the activation of NLRP3 inflammasome in a dose-dependent manner in macrophage, and that afatinib could prevent the assembly of NLRP3 inflammasome. Besides, afatinib could inhibit NLRP3 inflammasome activation independent of EGFR signaling. Moreover, afatinib was able to alleviate the LPS-induced sepsis in vivo. These investigations provide significant experimental evidence in afatinib as therapeutic drug for non-small cell lung cancer or other tumors and NLRP3-related diseases, and explore new target for afatinib in macrophage.

Keywords: EGFR; Inflammasome; NLRP3; TKI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afatinib* / pharmacology
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • ErbB Receptors
  • Humans
  • Inflammasomes / metabolism
  • Lung Neoplasms* / pathology
  • Macrophages / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Tyrosine Kinase Inhibitors / pharmacology

Substances

  • Afatinib
  • ErbB Receptors
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Tyrosine Kinase Inhibitors