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

Abstract

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 GPI 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.

Dust induces lung fibrosis through dysregulated DNA methylation

“…Thy‐1 (CD90) is a cell surface glycoprotein that is expressed on the surface of thymocytes, mesenchymal stem cells, hematopoietic stem cells, natural killer cells, neurons, endothelial cells, fibroblasts and myofibroblasts . It is involved in cell–cell–matrix interaction, and it regulates fibrosis, promotes cell migration and adhesion . In the process of fibrosis, Thy‐1 can inhibit fibroblast trans‐differentiation and inhibit fibrosis by correlating with TGF‐β, which is called “fibrosis inhibitory gene”.…”

Thy‐1: more than a marker for mesenchymal stromal cells

“…In summary, Thy-1 restricts myofibroblast differentiation and favors the resolution of fibrosis by initiating myofibroblast apoptosis in the lungs, which leads to the termination of reparative responses upon injury (27).…”

“…The reduced apoptosis of Thy-1-negative myofibroblasts led to the persistence of myofibroblasts and collagen accumulation during the resolution phase of bleomycininduced fibrosis, resulting in an extended lung fibrosis in Thy-1-deficient mice (27). Most importantly, in vitro data and mouse studies were validated by the fact that the majority of fibroblasts in healthy human lung express Thy-1; however, Thy-1 expression is lost in the fibroblastic foci of idiopathic pulmonary fibrosis (28,43,44).…”

“…Thy-1 can also interact with molecules within the membrane of the same cell (cis). In lung fibroblasts, a colocalization of Thy-1 with Fas (CD95) in lipid rafts promotes lung fibroblast susceptibility to apoptosis (27). Zhou et al reported that Thy-1 interacts with integrin avb5 on lung fibroblasts and prevents contractioninduced, integrin avb5-dependent, latent TGF-b1 activation and myofibroblast differentiation.…”

“…Obviously, the high expression of Thy-1, its localization in lipid rafts, and high carbohydrate content allow its interaction with different receptors, which results in the control of their activity. By acting in cis or trans, Thy-1 is able to interfere with several signaling pathways, including Smad, wingless-type mouse mammary tumor virus integration site (Wnt), Src, notch, and peroxisome proliferator-activated receptor g (Pparg) (22,26,27,(29)(30)(31)(32)(33)(34).…”