PTPN2 alleviates Silicotic pulmonary fibrosis by inhibiting senescence of type II alveolar epithelial cells via retinol metabolism regulated by ALDH1A2.

Abstract

The role and mechanism of protein tyrosine phosphatase non-receptor type 2 (PTPN2) in silicosis remain unclear. In this study, transcriptome sequencing, microcomputed tomography, histological examination, and western blot analysis were used to evaluate the effects of PTPN2 on the retinol metabolism signaling pathway, the transforming growth factor-beta 1 (TGF-β1) signaling pathway, cellular senescence, and pulmonary fibrosis in silicosis. The results demonstrated that overexpression of PTPN2 significantly reduced the degree of pulmonary fibrosis in silicosis model mice, whereas alveolar endothelial cell-specific knockout of PTPN2 exacerbated fibrosis. PTPN2 overexpression ameliorated fibrosis by regulating key enzymes in retinol metabolism, downregulating the TGF-β1 signaling pathway, and decreasing the expression of senescence-related signals. Both in vitro and in vivo results showed that PTPN2 overexpression upregulated the expression of retinol metabolism signaling pathway-related molecules (ALDH1A2, RDH10, and DHRS3), reversed the expression of TGF-β1 signaling pathway-related components (TGF-β1, TGF-βR1, and TGF-βR2) and the phosphorylation of Smad2/3, and downregulated the expression of senescence-associated factors (β-galactosidase, p-p53, p21, and p16). These findings suggest that PTPN2 may alleviate silicotic pulmonary fibrosis by inhibiting the senescence of type II alveolar epithelial cells via influencing retinol metabolism regulated by ALDH1A2.