Integrin Modulating Therapies Prevent Fibrosis and Autoimmunity in Genetic Mouse Models of Scleroderma

In systemic sclerosis (SSc), a common and etiologically mysterious form of scleroderma (defined as pathologic fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies [1]. Familial recurrence is extremely rare and causal genes have not been identified. While the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown [2]. The study of SSc is hindered by a lack of animal models that recapitulate the etiology of this complex disease. To gain a foothold in the pathogenesis of pathologic skin fibrosis, we chose to study stiff skin syndrome (SSS), a rare but tractable Mendelian disorder that shows childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the major constituent of extracellular microfibrils [3]. Notably, SSS mutations all localize to the only domain in fibrillin-1 that harbors an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins [3]. Here we show that mouse lines that harbor analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGFβ). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic, T helper, and plasma cells, and autoantibody production; these findings are normalized by integrin-modulating therapies or TGFβ antagonism. These data show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programs and highlight novel therapeutic strategies.