Thy-1 interaction with Fas in lipid rafts regulates fibroblast apoptosis and lung injury resolution

Lab Invest. 2017 Mar;97(3):256-267. doi: 10.1038/labinvest.2016.145. Epub 2017 Feb 6.


Thy-1-negative lung fibroblasts are resistant to apoptosis. The mechanisms governing this process and its relevance to fibrotic remodeling remain poorly understood. By using either sorted or transfected lung fibroblasts, we found that Thy-1 expression is associated with downregulation of anti-apoptotic molecules Bcl-2 and Bcl-xL, as well as increased levels of cleaved caspase-9. Addition of rhFasL and staurosporine, well-known apoptosis inducers, caused significantly increased cleaved caspase-3, -8, and PARP in Thy-1-transfected cells. Furthermore, rhFasL induced Fas translocation into lipid rafts and its colocalization with Thy-1. These in vitro results indicate that Thy-1, in a manner dependent upon its glycophosphatidylinositol anchor and lipid raft localization, regulates apoptosis in lung fibroblasts via Fas-, Bcl-, and caspase-dependent pathways. In vivo, Thy-1 deficient (Thy1-/-) mice displayed persistence of myofibroblasts in the resolution phase of bleomycin-induced fibrosis, associated with accumulation of collagen and failure of lung fibrosis resolution. Apoptosis of myofibroblasts is decreased in Thy1-/- mice in the resolution phase. Collectively, these findings provide new evidence regarding the role and mechanisms of Thy-1 in initiating myofibroblast apoptosis that heralds the termination of the reparative response to bleomycin-induced lung injury. Understanding the mechanisms regulating fibroblast survival/apoptosis should lead to novel therapeutic interventions for lung fibrosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Bleomycin
  • Caspase 9 / metabolism
  • Cell Line
  • Embryo, Mammalian / cytology
  • Fas Ligand Protein / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Immunoblotting
  • Lung Injury / chemically induced
  • Lung Injury / metabolism*
  • Lung Injury / prevention & control
  • Membrane Microdomains / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / prevention & control
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Staurosporine / pharmacology
  • Thy-1 Antigens / genetics
  • Thy-1 Antigens / metabolism*
  • bcl-X Protein / metabolism
  • fas Receptor / metabolism*


  • Fas Ligand Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Thy-1 Antigens
  • bcl-X Protein
  • fas Receptor
  • Bleomycin
  • Caspase 9
  • Staurosporine