Non-immune cells can also respond to inflammatory stimuli via TLRs, including epithelial cells, fibroblasts, endothelial cells and adipocytes ( Faure et al., 2000 Guillot et al., 2004 Kollisch et al., 2005 Morris et al., 2006). Toll-like receptors (TLRs) have emerged as commonly used sensors for innate immune activation through recognition of common molecular patterns found on microbes ( Akira et al., 2006). Although these models have shown that inflammatory changes may underlie fibrosis, and have many useful features that overlap pathological, immune and fibrotic feature of SSc skin, they have not proven readily tractable for examining the role of innate immunity in mediating skin fibrosis. Dermal fibrosis induced by subcutaneous injection of bleomycin, and in the chronic graft versus host disease murine models of SSc is dependant on TGFβ ( Yamamoto et al., 1999 Zhang et al., 2002 Zhang et al., 2003), and bleomycin-induced fibrosis at least partially dependent on IL-13 ( Aliprantis et al., 2007 Seki et al., 2007). Less is known about the relationship between inflammation and fibrosis of skin. TGFβ, when inducibly expressed in the lung in its active form, induces inflammation and fibrosis ( Lee et al., 2004). Mice overexpressing IL-13 develop ILD, dependent on enhanced MMP9 activation of TGFβ ( Lee et al., 2001). IL-13 contributes to fibrosis in bleomycin-induced ILD and induces fibrosis itself in IL-13 transgenic mice ( Belperio et al., 2002). IL-13 and TGFβ have been most strongly implicated in linking inflammation and fibrosis. Autoantibodies and elevated circulating immune mediators further indicate immune activation. Perivascular and deep dermal inflammatory cell infiltrates are also features of SSc skin. Transforming growth factor-β (TGFβ) has been strongly implicated in SSc-associated fibrosis: it potently induces collagen and collagen processing, it transforms fibroblasts into profibrotic myofibroblasts and it regulates genes key to pathologic fibrosis ( Jelaska and Korn, 2000 Kissin et al., 2006). Systemic sclerosis (SSc) has interrelated pathogenic features involving immune activation and fibrosis. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, potentially mediated by TLR3 or other innate immune receptors. However, in this model type I IFNs played no apparent role regulating TGFβ activity in the skin. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. The TLR3 ligand, Poly(I:C), mostly highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. We found that expression of both IFN- and TGFβ-responsive genes are increased in SSc skin and in SSc fibroblasts when stimulated by TLR ligands. To better understand the relationship between inflammation and fibrosis in vivo we developed a murine model for chronic innate immune stimulation. The goal of this study was to better understand innate immune regulation and associated IFN- and TGFβ-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. Immune activation of fibrosis likely plays a crucial role in the pathogenesis of systemic sclerosis (SSc).
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