Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Transfers
  • Current issue
  • Past issues
  • By specialty
  • Contact
  • Recently published
  • Technical Advances
  • Clinical Medicine
  • Editorials
  • Top read articles
Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif
Chunting Tan, … , Edward Connors, James S. Hagood
Chunting Tan, … , Edward Connors, James S. Hagood
Published November 1, 2019
Citation Information: JCI Insight. 2019;4(21):e131152. https://doi.org/10.1172/jci.insight.131152.
View: Text | PDF
Categories: Research Article Pulmonology

Soluble Thy-1 reverses lung fibrosis via its integrin-binding motif

  • Text
  • PDF
Abstract

Loss of Thy-1 expression in fibroblasts correlates with lung fibrogenesis; however, the clinical relevance of therapeutic targeting of myofibroblasts via Thy-1–associated pathways remains to be explored. Using single (self-resolving) or repetitive (nonresolving) intratracheal administration of bleomycin in type 1 collagen-GFP reporter mice, we report that Thy-1 surface expression, but not mRNA, is reversibly diminished in activated fibroblasts and myofibroblasts in self-resolving fibrosis. However, Thy-1 mRNA expression is silenced in lung with nonresolving fibrosis following repetitive bleomycin administration, associated with persistent activation of αv integrin. Thy1-null mice showed progressive αv integrin activation and myofibroblast accumulation after a single dose of bleomycin. In vitro, targeting of αv integrin by soluble Thy-1-Fc (sThy-1), but not RLE-mutated Thy-1 or IgG, reversed TGF-β1–induced myofibroblast differentiation in a dose-dependent manner, suggesting that Thy-1’s integrin-binding RGD motif is required for the reversibility of myofibroblast differentiation. In vivo, treatment of established fibrosis induced either by single-dose bleomycin in WT mice or by induction of active TGF-β1 by doxycycline in Cc10-rtTA-tTS-Tgfb1 mice with sThy-1 (1000 ng/kg, i.v.) promoted resolution of fibrosis. Collectively, these findings demonstrate that sThy-1 therapeutically inhibits the αv integrin–driven feedback loop that amplifies and sustains fibrosis.

Authors

Chunting Tan, Min Jiang, Simon S. Wong, Celia R. Espinoza, Ceonne Kim, Xiaoping Li, Edward Connors, James S. Hagood

×

Figure 5

Soluble Thy-1 reverses myofibroblastic differentiation of senescent human lung myofibroblasts in a dose-dependent manner in vitro.

Options: View larger image (or click on image) Download as PowerPoint
Soluble Thy-1 reverses myofibroblastic differentiation of senescent huma...
Human lung fibroblasts (CCL-210) were incubated with human TGF-β1 (10 ng/ml for 48 hours) and subsequently subjected to 5-day serum-free media to induce senescence (n = 4/group, 3 times). (A) Myofibroblast differentiation and senescence were validated by qPCR of Acta2, Col1α1, and p21. (B) qPCR for Acta2 and Col1α1 after treatment of myofibroblasts with sThy-1-IgG Fc (10, 100, 1000 ng/mL), Thy-1(RLE)-IgG Fc (1000 ng/ml), or IgG Fc (1000 ng/ml) for 48 hours. (C) Western blot (WB) of αSMA expression. (D) WB quantification. Results are presented as mean ± SEM. Statistical analysis was performed using 2-tailed Student’s t test and 1-way ANOVA; *P < 0.05, **P < 0.01.
Follow JCI Insight:
Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts