Activating GLP-1R with liraglutide attenuated pulmonary inflammation and fibrosis in mice exposed to silica.
GLP-1R activation may reduce fibroblast activation in response to TGF-β1 and IL-1β.
Inhibition of the is associated with decreased glycolysis and lactate production in lung fibroblasts.
Liraglutide disrupts the interaction between the NLRP3 inflammasome and glycolysis, leading to lower expression of pro-fibrotic genes.
GLP-1R activation may protect mitochondria from oxidative stress in lung fibroblasts caused by TGF-β1 and IL-1β.
In lactate-treated lung fibroblasts, GLP-1R activation could repress NLRP3 inflammasome activation and .
Simplified
BACKGROUND: Pulmonary fibrosis is a serious interstitial lung disease with no viable treatment except for lung transplantation. Glucagon-like peptide-1 receptor (GLP-1R), commonly regarded as an antidiabetic target, exerts antifibrotic effects on various types of organ fibrosis. However, whether GLP-1R modulates the development and progression of pulmonary fibrosis remains unclear. In this study, we investigated the antifibrotic effect of GLP-1R using in vitro and in vivo models of pulmonary fibrosis.
METHODS: A silica-induced pulmonary fibrosis mouse model was established to evaluate the protective effects of activating GLP-1R with liraglutide in vivo. Primary cultured lung fibroblasts treated with TGF-β1 combined with IL-1β (TGF-β1 + IL-1β) were used to explore the specific effects of liraglutide, MCC950, and 3PO on fibroblast activation in vitro. Cell metabolism assay was performed to determine the glycolytic rate and mitochondrial respiration. RNA sequencing was utilized to analyse the underlying molecular mechanisms by which liraglutide affects fibroblast activation. ChIP‒qPCR was used to evaluate at the promoters of profibrotic genes in TGF-β1 + IL-1β- or exogenous lactate-stimulated lung fibroblasts.
RESULTS: Activating GLP-1R with liraglutide attenuated pulmonary inflammation and fibrosis in mice exposed to silica. Pharmacological inhibition of the suppressed -driven glycolysis and vice versa, resulting in decreased lactate production in TGF-β1 + IL-1β-stimulated lung fibroblasts. Activating GLP-1R inhibited TGF-β1 + IL-1β-induced fibroblast activation by disrupting the interaction between the NLRP3 inflammasome and PFKFB3-driven glycolysis and subsequently prevented lactate-mediated histone lactylation to reduce pro-fibrotic gene expression. In addition, activating GLP-1R protected mitochondria against the TGF-β1 + IL-1β-induced increase in oxidative phosphorylation in fibroblasts. In exogenous lactate-treated lung fibroblasts, activating GLP-1R not only repressed NLRP3 inflammasome activation but also alleviated p300-mediated histone lactylation. Finally, GLP-1R activation blocked silica-treated macrophage-conditioned media-induced lung fibroblast activation.
CONCLUSIONS: The antifibrotic effects of GLP-1R activation on pulmonary fibrosis could be attributed to the inhibition of the interaction between NLRP3 inflammasome and PFKFB3-driven glycolysis, and histone lactylation in lung fibroblasts. Thus, GLP-1R is a specific therapeutic target for the treatment of pulmonary fibrosis.
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