1. Academic Validation
  2. PD-L1 mediates lung fibroblast to myofibroblast transition through Smad3 and β-catenin signaling pathways

PD-L1 mediates lung fibroblast to myofibroblast transition through Smad3 and β-catenin signaling pathways

  • Sci Rep. 2022 Feb 23;12(1):3053. doi: 10.1038/s41598-022-07044-3.
Xia Guo  # 1 Christudas Sunil  # 1 Oluwaseun Adeyanju 1 Andrew Parker 1 Steven Huang 2 Mitsuo Ikebe 1 Torry A Tucker 1 3 Steven Idell 1 3 Guoqing Qian 4
Affiliations

Affiliations

  • 1 Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX, 75708, USA.
  • 2 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine at the University of Michigan, Ann Arbor, USA.
  • 3 The Texas Lung Injury Institute, Tyler, TX, USA.
  • 4 Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX, 75708, USA. guoqing.qian@uthct.edu.
  • # Contributed equally.
Abstract

Programmed death ligand-1 (PD-L1) is an immune checkpoint protein that has been linked with idiopathic pulmonary fibrosis (IPF) and fibroblast to myofibroblast transition (FMT). However, it remains largely unclear how PD-L1 mediates this process. We found significantly increased PD-L1 in the lungs of idiopathic pulmonary fibrosis patients and mice with pulmonary fibrosis induced by bleomycin and TGF-β. In primary human lung fibroblasts (HLFs), TGF-β induced PD-L1 expression that is dependent on both SMAD3 and p38 pathways. PD-L1 knockdown using siRNA significantly attenuated TGF-β-induced expression of myofibroblast markers α-SMA, collagen-1, and fibronectin in normal and IPF HLFs. Further, we found that PD-L1 interacts with SMAD3, and TGF-β induces their interaction. Interestingly, PD-L1 knockdown reduced α-SMA reporter activity induced by TGF-β in HLFs, suggesting that PD-L1 might act as a co-factor of SMAD3 to promote target gene expression. TGF-β treatment also phosphorylates GSK3β and upregulates β-catenin protein levels. Inhibiting β-catenin signaling with the pharmaceutical inhibitor ICG001 significantly attenuated TGF-β-induced FMT. PD-L1 knockdown also attenuated TGF-β-induced GSK3β phosphorylation/inhibition and β-catenin upregulation, implicating GSK3β/β-catenin signaling in PD-L1-mediated FMT. Collectively, our findings demonstrate that fibroblast PD-L1 may promote pulmonary fibrosis through both SMAD3 and β-catenin signaling and may represent a novel interventional target for IPF.

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