Title: Role of Matrix Proteins in Balancing Tissue Stiffness and Inflammation in Fibrosis
Abstract: Fibrosis, the accumulation of excessive and disordered extracellular matrices (ECMs), is a pathological feature of many diseases leading to organ scarring and failure. Fibrosis affects most organs and contributes to approximately one third of natural deaths worldwide. Fibrosis appears to usurp a normal wound healing response in which fibroblast activation and deposition of a controlled amount of ECM and its remodeling are required for the proper repair of damaged tissues. An altered wound healing response, characterized by aberrant and sustained activation of fibroblasts, often leads to fibrosis. Although the underlying mechanisms are mostly unknown, altered physicochemical properties of the ECM has been considered as a contributor to fibrosis, rather than merely a manifestation of the disease. Here, we show that the loss of Fibulin-5, an elastic fiber component, not only decreases mechanical properties of the tissue, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis. Our studies further show that Fibulin- 5 could be an effective therapeutic target to short-circuit this self-sustaining, profibrotic feedback loop, and thereby resolving fibrogenesis.