Protein tyrosine phosphatase-α amplifies transforming growth factor-β-dependent profibrotic signaling in lung fibroblasts

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrosing lung disease for which treatment remains suboptimal. Fibrogenic cytokines, including transforming growth factor-β, are central to its pathogenesis. Protein Tyrosine Phosphatase-alpha (PTPα) has emerged as a key regulator of fibrogenic signaling in fibroblasts. We have reported that mice globally deficient in PTPα (Ptpra-/-) were protected from experimental pulmonary fibrosis, in part via alterations in TGF-β signaling. The goal of this study was to determine the lung cell types and mechanisms by which PTPα controls fibrogenic pathways and whether these pathways are relevant to human disease. Immunohistochemical analysis of lungs from IPF patients revealed that PTPα was highly expressed by mesenchymal cells in fibroblastic foci and by airway and alveolar epithelial cells. To determine whether PTPα promotes profibrotic signaling pathways in lung fibroblasts and/or epithelial cells, we generated mice with conditional (floxed) Ptpra alleles (Ptpraf/f). These mice were crossed with Dermo1-Cre or with Sftpc-CreERT2 mice to delete Ptpra in mesenchymal cells and alveolar type (AT) II cells, respectively. Dermo1-Cre/Ptpraf/f mice were protected from bleomycin-induced pulmonary fibrosis, while Sftpc-CreERT2/Ptpraf/f mice developed pulmonary fibrosis equivalent to controls. Both canonical and non-canonical TGF-β signaling and downstream TGF-β-induced fibrogenic responses were attenuated in isolated Ptpra-/- compared to wild type fibroblasts. Further, TGF-β-induced tyrosine phosphorylation of TGF-βRII and of PTPα was attenuated in Ptpra-/- compared to WT fibroblasts. The phenotype of cells genetically deficient in PTPα was recapitulated with the use of a Src inhibitor. These findings suggest that PTPα amplifies pro-fibrotic TGF-β-dependent pathways signaling in lung fibroblasts.

ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation

“…In this study, we investigated the expression of CB 1 R in lung fibroblasts isolated from BLM-challenged mice and found that CB 1 R mRNA levels were significantly increased in the isolated lung fibroblasts from mice with BLM-induced pulmonary fibrosis compared with control mice ( Figure 3A ), which is in accordance with the increased CB 1 R mRNA levels in lung tissues of pulmonary fibrosis mice ( Figure 1A ). TGF-β1 is one of the most potent and well-studied profibrotic inducers of pulmonary fibrosis that triggers and greatly enhances the fibrogenic activity of lung fibroblasts ( Fernandez and Eickelberg, 2012 ; Martinez et al, 2017 ; Aschner et al, 2020 ; Lee et al, 2020 ). We isolated primary mouse lung fibroblasts to examine the expression of CB 1 R and ECM proteins induced by TGF-β1.…”

“…In the pathogenesis of pulmonary fibrosis, lung fibroblasts are activated under the stimulation of profibrotic cytokines and exhibit a series of cell behavior changes, such as proliferation, migration, and ECM production, which is associated with severity of the disease in patients with pulmonary fibrosis and mouse models of pulmonary fibrosis ( Xia et al, 2014 ; DePianto et al, 2015 ; Kasam et al, 2020 ). TGF-β family proteins, especially TGF-β1, released by injured lung epitheliums, immune cells, and fibrocytes during pulmonary fibrosis, are considered the principal profibrotic cytokines that drives fibrotic responses ( Fernandez and Eickelberg, 2012 ; Martinez et al, 2017 ; Aschner et al, 2020 ; Lee et al, 2020 ). TGF-β signals are generally transduced through TGF-β type I and type II receptors (TβRI and TβRII) and Smads, and ancillary proteins as well ( Aschner et al, 2020 ; Lee et al, 2020 ).…”

“…TGF-β family proteins, especially TGF-β1, released by injured lung epitheliums, immune cells, and fibrocytes during pulmonary fibrosis, are considered the principal profibrotic cytokines that drives fibrotic responses ( Fernandez and Eickelberg, 2012 ; Martinez et al, 2017 ; Aschner et al, 2020 ; Lee et al, 2020 ). TGF-β signals are generally transduced through TGF-β type I and type II receptors (TβRI and TβRII) and Smads, and ancillary proteins as well ( Aschner et al, 2020 ; Lee et al, 2020 ). Although TGF-β signals are attractive targets for lung fibrosis, genetic and pharmacological studies have indicated that broad targeting of general TGF-β signaling pathways might be problematic for treating fibrotic disease due to the pleiotropic roles of TGF-β ( Mora et al, 2017 ; Saito et al, 2018 ).…”

Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway

“…In contrast, DEC1 overexpression induced EMT in vitro . TGF-β1, a crucial mediator in tissue fibrosis, is a significant factor in promoting EMT and the development of PF ( Akhurst and Hata, 2012 ; Aschner et al, 2020 ). We also found that Dec1 KO alleviated BLM-induced upregulated expression of TGF-β1 in BALF in mice.…”

Pulmonary fibrosis: something old, something new…still waiting for a breakthrough

“…There has been renewed interest in molecules such as members of the cellular communication network (CCN) ( 12 ) and the insulin-like growth factor (IGF) ( 3 , 22 ) family of proteins and their functions in the setting of lung fibrosis. Moonlighting functions for enzymes such as sialidases ( 11 ) and phosphatases ( 1 , 18 , 21 ) have been identified. Research into mechanisms mediating oxidative stress and its role in lung fibrosis has continued ( 6 ).…”