Thy-1-Integrin αvβ5 Interactions Inhibit Lung Fibroblast Contraction-induced Latent Transforming Growth Factor-β1 Activation and Myofibroblast Differentiation

Abstract

Myofibroblasts, key effector cells in tissue fibrosis, are specialized contractile cells. Lung myofibroblast contraction induces integrin ␣ v ␤ 5 -dependent latent transforming growth factor (TGF)-␤1 activation suggests that myofibroblast contractility may be a driving force for the persistent myofibroblast differentiation observed in fibrotic lungs. Understanding the mechanisms that regulate fibroblast contraction and mechanotransduction will add new insights into the pathogenesis of lung fibrosis and may lead to new therapeutic approaches for treating fibrotic lung diseases. We and others previously demonstrated that lung fibroblast expression of Thy-1 prevents lung fibrosis. The mechanisms underlying the anti-fibrotic effect of Thy-1 are not well understood. In this study, we showed that Thy-1 interacts with integrin ␣ v ␤ 5 , both in a cell-free system and on the cell surface of rat lung fibroblasts. Thy-1-integrin ␣ v ␤ 5 interactions are RLDdependent because mutated Thy-1, in which RLD is replaced by RLE, loses the ability to bind the integrin. Furthermore, Thy-1 expression prevents fibroblast contraction-induced, integrin ␣ v ␤ 5 -dependent latent TGF-␤1 activation and TGF-␤1-dependent lung myofibroblast differentiation. In contrast, lack of Thy-1 expression or disruption of Thy-1-␣ v ␤ 5 interactions renders lung fibroblasts susceptible to contraction-induced latent TGF-␤1 activation and myofibroblast differentiation. These data suggest that Thy-1-integrin ␣ v ␤ 5 interactions inhibit contraction-induced latent TGF-␤1 activation, presumably by blocking the binding of extracellular matrix-bound latent TGF-␤1 with integrin ␣ v ␤ 5 . Our studies suggest that targeting key mechanotransducers to inhibit mechanotransduction might be an effective approach to inhibit the deleterious effects of myofibroblast contraction on lung fibrogenesis.

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

“…Myofibroblasts expressing either CD90 or Pdpn have been observed in several settings, although CD90 interactions are reported to block fibrosis. 52,55,56 These a-SMA þ costaining patterns were often complex, yet consistent with a narrow focal plane through contorted, twisting cells (Supplemental Figure S5). Myofibroblasts run parallel to the fibers and like with CD34 þ SFC, the staining patterns are additionally dictated by the plane-ofsection of the fiber bundles.…”

Mechanisms of Lung Fibrosis Resolution

“…39 However, even if differentiation can be inhibited, persistent myofibroblasts can induce a feedforward mechanism for maintaining the myofibroblast phenotype and inducing neighboring cells into fibrotic and dysfunctional cells through mechanotransductionmediated up-regulation of profibrotic and prosurvival genes. 39,41,42 Therefore, elimination of embedded myofibroblasts is paramount to promoting resolution. There are three primary molecular mechanisms mediating myofibroblast removal: dedifferentiation, apoptosis, and senescence.…”

Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis

“…Thy-1 was implicated in the inhibition of TGF-β1 responses in tissue fibroblasts via interaction with αν-β5 integrins (38)(39)(40)(41)(42). While Thy-1 functions are not well characterized, deletion of Thy-1 in mice was shown to exacerbate bleomycin-induced lung fibrosis (36).…”