Systemic sclerosis immunoglobulin induces growth and a pro-fibrotic state in vascular smooth muscle cells through the epidermal growth factor receptor
Systemic sclerosis (SSc) is an autoimmune disease characterized by the presence of autoantibodies, fibrosis and vasculopathy. It has been suggested that autoantibodies in systemic sclerosis may induce the differentiation of cultured fibroblasts into myofibroblasts through platelet-derived growth factor receptor (PDGFR) activation. The present study aims to characterize the effects of SSc IgG on vascular smooth muscle cells (VSMCs) and to determine if stimulatory autoantibodies directed to the PDGFR can be detected, and whether they induce a profibrotic response in primary cultured VSMCs. Cultured VSMCs were exposed to IgG fractions purified from SSc-patient or control sera. VSMC responses were then analyzed for ERK1/2 and Akt phosphorylation, cellular proliferation, protein synthesis, and pro-fibrotic changes in mRNA expression. The capacity of the IgG fractions to immunoprecipitate the PDGFR from VSMC lysates was also tested. Stimulatory activity in IgG fractions was more prevalent and intense in the SSc samples than in the controls (p<0.05), and SSc IgG immunoprecipitated the PDGFR with greater avidity than control IgG. Interestingly, activation of downstream signaling events (Akt, ERK1/2) was independent of PDGFR activity, but required functional epidermal growth factor receptor (EGFR). We also detected increased protein synthesis (p<0.001) and pro-fibrotic changes in gene expression (Tgfb1 +200%; Tgfb2 -23%; p<0.001) in VSMCs treated with SSc IgG. When compared to control IgG, SSc IgG has a higher stimulation index in VSMCs. Although SSc IgG interact with the PDGFR, the observed remodeling signaling events occur through the EGFR in VSMC. Our data thus favour a model of transactivation of the EGFR by SSc-derived PDGFR autoantibodies and suggest the use of EGFR inhibitors in future target identification studies in the field of SSc.
Systemic sclerosis Scleroderma Vascular smooth muscle cells Autoantibodies Protein kinase inhibitors Receptor transactivation Platelet-derived growth factor receptor Epidermal growth factor receptor PDGFR EGFR