Versican expression from lung fibroblasts suppresses pulmonary fibrosis

The activation and accumulation of lung fibroblasts, leading to excessive ECM deposition, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and currently untreatable disease. In this report, increased expression of Versican, a multifunctional ECM proteoglycan, is detected in both human and mouse pulmonary fibrosis, mainly in monocytic cells and fibroblasts. Ubiquitous genetic reduction of Versican expression in mice promotes collagen expression and polymerisation, alters pulmonary ECM composition and structure, and exacerbates pulmonary fibrosis, delaying its resolution. Moreover, the decrease in Versican in the ECM and the ensuing reorganisation stimulate Tenascin-C expression from fibroblasts, which is further shown to be a potent Toll-like receptor 4-dependent podosome inducer, promoting ECM invasion. Thus, fibroblast-expressed Versican regulates the underlying ECM composition and structure and suppresses autologous podosome formation, limiting ECM invasion and pulmonary fibrosis. Idiopathic pulmonary fibrosis is characterised by the accumulation of fibroblasts, which deposit excessive extracellular matrix impairing respiratory functions. Here, the authors show that fibroblast-expressed versican, a chondroitin sulphate proteoglycan, suppresses fibroblasts’ ability to invade and further grow the underlying matrix, thus limiting their accumulation and attenuating pulmonary fibrosis.