Age-dependent susceptibility to pulmonary fibrosis is associated with NLRP3 inflammasome activation

Heather W. Stout-Delgado, Soo Jung Cho, Sarah G. Chu, Dana N. Mitzel, Julian Villalba, Souheil El-Chemaly, Stefan W. Ryter, Augustine M.K. Choi, Ivan O. Rosas

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Aging has been implicated in the development of pulmonary fibrosis, which has seen a sharp increase in incidence in those older than 50 years. Recent studies demonstrate a role for the nucleotidebinding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome and its regulated cytokines in experimental lung fibrosis. In this study, we tested the hypothesis that age-related NLRP3 inflammasome activation is an important predisposing factor in the development of pulmonary fibrosis. Briefly, young and aged wild-type and NLRP3-/- mice were subjected to bleomycin-induced lung injury. Pulmonary fibrosis was determined by histology and hydroxyproline accumulation. Bone marrow and alveolar macrophages were isolated from these mice. NLRP3 inflammasome activation was assessed by co-immunoprecipitation experiments. IL-1band IL-18 production was measured by ELISA. The current study demonstrated that aged wild-type mice developed more lung fibrosis and exhibited increased morbidity and mortality after bleomycin-induced lung injury, when compared with young mice. Bleomycin-exposed aged NLRP3-/- mice had reduced fibrosis compared with their wild-type age-matched counterparts. Bone marrow-derived and alveolar macrophages from aged mice displayed higher levels of NLRP3 inflammasome activation and caspase-1-dependent IL-1b and IL-18 production, which was associated with altered mitochondrial function and increased production of reactive oxygen species. Our study demonstrated that age-dependent increases in alveolar macrophage mitochondrial reactive oxygen species production and NLRP3 inflammasome activation contribute to the development of experimental fibrosis.

Original languageEnglish (US)
Pages (from-to)252-263
Number of pages12
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume55
Issue number2
DOIs
StatePublished - Aug 2016

Keywords

  • Aging; bleomycin; mitochondrial oxidative stress; NLRP3 inflammasome; pulmonary fibrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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