Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription

Abstract

Determining the mechanism of senescence‐associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence‐associated pulmonary fibrosis by activating TGF‐β1/IL‐11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF‐β1/IL‐11/MEK/ERK signaling‐mediated senescence‐associated pulmonary fibrosis in vitamin D‐deficient ( Cyp27b1 ^−/− ) mice, and whether Sirt1 downregulated IL‐11 expression transcribed by TGF‐β1/Smad2 signaling through deacetylating histone at the IL‐11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild‐type (WT) mice were examined for cell senescence, fibrosis markers, and TGF‐β1/IL‐11/MEK/ERK signaling proteins, and 1,25(OH) ₂D ₃ and IL‐11 levels were detected in serum. Nine‐week‐old WT, Sirt1 mesenchymal transgene ( Sirt1 ^Tg ), Cyp27b1 ^−/− , and Sirt1 ^Tg Cyp27b1 ^−/− mice were observed the pulmonary function, aging, and senescence‐associated secretory phenotype and TGF‐β1/IL‐11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF‐β1/IL‐11/MEK/ERK signaling, and promoting senescence‐associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence‐associated secretory phenotype, and fibrosis through downregulating TGF‐β1/IL‐11/MEK/ERK signaling in Cyp27b1 ^−/− mice. Sirt1 negatively regulated IL‐11 expression through deacetylating H3K9/14ac mainly at the region from −871 to −724 of IL‐11 promoter, also the major binding region of Smad2 which regulated IL‐11 expression at the transcriptional level, and subsequently inhibiting TGF‐β1/IL‐11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence‐associated pulmonary fibrosis induced by vitamin D deficiency.

Abstract

Pulmonary Sirt1 and serum vitamin D (VD) decrease with physiological aging, activating TGF‐β1/IL‐11/MEK/ERK (TIME) signaling and promoting senescence‐associated pulmonary fibrosis (SAPF). Sirt1 overexpression ameliorates SAPF in VD‐deficient mice through downregulating IL‐11 transcribed by Smad2 via deacetylating H3K9/14ac mainly at the region from −871 to −724 of IL‐11 promoter, and subsequently inhibiting TIME signaling in pulmonary fibroblasts. This signal in aging fibroblasts could be a therapeutic target for preventing physiologically VD deficiency‐induced SAPF.