NLRP3 inflammasome activation contributes to the development of the pro-fibrotic phenotype of lung fibroblasts

Biochem Pharmacol. 2024 Nov:229:116496. doi: 10.1016/j.bcp.2024.116496. Epub 2024 Aug 17.

Abstract

Idiopathic pulmonary fibrosis (IPF) is an irreversible progressive interstitial lung disease of unknown cause. The poorly understood pathophysiology of IPF poses substantial challenges to the development of effective anti-lung fibrotic drugs. The NLRP3 inflammasome, a key component of the innate immune system, has recently been linked to the pathogenesis of lung fibrosis. However, the specific contributions of NLRP3 inflammasomes to determination of the pro-fibrotic phenotype of lung fibroblasts, which play a central role in the production of extracellular matrix protein, remain to be investigated. Therefore, the present study was performed to elucidate the involvement of NLRP3 inflammasome signalling pathways in modulation of lung fibroblast proliferation and differentiation. We found that activation of NLRP3 inflammasomes increased in lung fibroblasts derived from individuals with pulmonary fibrosis and in normal lung fibroblasts stimulated with transforming growth factor β and platelet-derived growth factor. Importantly, blockage of NLRP3 inflammasome signalling, either by gene silencing of NLRP3 or using pharmacological inhibitors of NLRP3, caspase-1, or IL-1 receptor, inhibited the proliferation, differentiation, and extracellular matrix protein synthesis of activated lung fibroblasts. Moreover, induction of the reactive oxygen species/thioredoxin-interacting protein axis, an upstream signalling pathway of NLRP3 inflammasomes, was essential for maintenance of the pro-fibrotic phenotype of lung fibroblasts. Interestingly, treatments with pharmacological inhibitors of NLRP3 inflammasomes prevented the progression of bleomycin-induced pulmonary fibrosis in mice. Collectively, these findings suggest that aberrant activation of NLRP3 inflammasomes is a critical event in the pathogenesis of IPF and that targeting NLRP3 inflammasomes may serve as a therapeutic strategy for IPF.

Keywords: Fibroblasts; Inflammasomes; MCC950; NLRP3; Pulmonary fibrosis; TGFβ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / toxicity
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Fibroblasts* / drug effects
  • Fibroblasts* / metabolism
  • Fibroblasts* / pathology
  • Humans
  • Idiopathic Pulmonary Fibrosis / immunology
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology
  • Inflammasomes* / metabolism
  • Lung* / drug effects
  • Lung* / immunology
  • Lung* / metabolism
  • Lung* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Phenotype

Substances

  • Bleomycin
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human