Mechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis

Abstract

Matrix stiffening is a prominent feature of pulmonary fibrosis. In this study, we demonstrate that matrix stiffness regulates the ability of fibrotic lung myofibroblasts to invade the basement membrane (BM). We identify α6-integrin as a mechanosensing integrin subunit that mediates matrix stiffness-regulated myofibroblast invasion. Increasing α6-expression, specifically the B isoform (α6B), couples β1-integrin to mediate MMP-2-dependent pericellular proteolysis of BM collagen IV, leading to myofibroblast invasion. Human idiopathic pulmonary fibrosis lung myofibroblasts express high levels of α6-integrin in vitro and in vivo. Genetic ablation of α6 in collagen-expressing mesenchymal cells or pharmacological blockade of matrix stiffness-regulated α6-expression protects mice against bleomycin injury-induced experimental lung fibrosis. These findings suggest that α6-integrin is a matrix stiffness-regulated mechanosensitive molecule which confers an invasive fibroblast phenotype and mediates experimental lung fibrosis. Targeting this mechanosensing α6(β1)-integrin offers a novel anti-fibrotic strategy against lung fibrosis.

3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

“…Podosomes or invadopodia lead invading fibroblasts with activation of cell surface proteases and remodeling of the ECM (12,27,28). A recent study from our group demonstrated that mechanosensing of stiffened matrix by β 6 integrins confers an invasive phenotype of IPF lung myofibroblasts and mediates experimental lung fibrosis (29). IPF is also characterized by basement membrane destruction, which allows fibroblasts to invade into the provisional matrices that develop in alveoli after injury.…”

Integrin α6and EGFR Signaling Converge at Mechanosensitive Calpain 2

“…As two examples, the expression of integrins α 2 , α 3 , and β 1 is higher in mouse mammary epithelial cells cultured on TCPS compared to cells on a soft basement membrane-like matrix [50], and integrin α 5 expression was found to increase 5-fold on a 10 kPa stiffness compared to 1 kPa in cancer cells [17] and over a similar range in fibroblasts [63]. Most of this work has focused on collagen-and fibronectin-binding integrins, with the exception of one paper on integrin α 6 in fibroblasts, where expression increased with stiffness, resulting in increased invasion [64]. We demonstrate here the mechanosensitivity of integrin α 6 in breast cancer cells, and the downstream regulation of cell adhesion, migration, and response to EGF (Fig.…”

TRPV4—A Missing Link Between Mechanosensation and Immunity

“…Conversely, activation of protease-activated receptor (PAR)-2 by thrombin suppresses TRPV4 activity in macrophages and resolves lung injury (74). Similarly, PARs are also activated by neutrophil elastase (NE), matrix metalloproteases (MMPs) or other microbial proteases (33,(75)(76)(77)(78)(79) which has been implicated to degrade ECM and thereby causing remodeling and matrix stiffening during infection (33,63,73,80).…”