Poly(I:C) Drives Type I IFN- and TGFβ-Mediated Inflammation and Dermal Fibrosis Simulating Altered Gene Expression in Systemic Sclerosis

Immune activation of fibrosis likely has a crucial role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-beta (TGF beta)-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo, we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGF beta-responsive genes is increased in SSc skin and SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGF beta-responsive gene expression. Of the TLRs ligands tested, the TLR3 ligand, polyinosinic/polycytidylic acid (Poly(I: C)), most highly increased fibroblast expression of both IFN- and TGF beta-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I: C) stimulated inflammation, and IFN- and TGF beta-responsive gene expression. However, in this model, type I IFNs had no apparent role in regulating TGF beta activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors.