Age-dependent susceptibility to pulmonary fibrosis is associated with NLRP3 inflammasome activation
HW Stout-Delgado, SJ Cho, SG Chu… - American journal of …, 2016 - atsjournals.org
HW Stout-Delgado, SJ Cho, SG Chu, DN Mitzel, J Villalba, S El-Chemaly, SW Ryter…
American journal of respiratory cell and molecular biology, 2016•atsjournals.orgAging 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 nucleotide-binding 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 …
sharp increase in incidence in those older than 50 years. Recent studies demonstrate a role
for the nucleotide-binding 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 …
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 nucleotide-binding 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-1β and 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-1β 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.
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