Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disorder that can result in extensive tissue damage in the skin and, in advanced cases, internal organs. Vasculopathy, aberrant immune activation, and tissue fibrosis are three hallmarks of the disease that have been identified, with vasculopathy and aberrant immunity being amongst the earliest events. However, a mechanistic link between these processes has not been established. Here, we have identified a novel role of platelet derived growth factor-BB (PDGF-BB)/PDGFRβ activation in combination with dermal injury induced by bleomycin as a driver of early, aberrant expression of interferon stimulatory genes (ISGs) and inflammatory monocyte infiltration. Activation of PDGFRβ in combination with bleomycin-induced dermal injury resulted in increased dermal thickness, vascular density, monocyte/macrophage infiltration, and exacerbation of tissue injury. Many of these features were dependent on IFNAR-signaling, and an increase in the number of interferon-beta (IFN-β) producing monocytes cells was found in the skin lesions. Taken together, these results identify a novel link between PDGFRβ activation, and Type I IFN-driven vascular maintenance and monocyte/macrophage cell recruitment, and provide a potential explanation linking key features of SSc that were previously thought to be unrelated.
Highlights
Systemic sclerosis (SSc) is a complex multi-system autoimmune disease with three distinct pathologies that define the disease, namely: vasculopathy, aberrant immune activation, and tissue fibrosis [1]
While vasculopathy and aberrant immune activation occur in early stages of SSc, the advanced stages are marked by tissue fibrosis that develops in the skin and can progress to other organs, leading to mortality
To determine if PDGFRβ activation in the skin could alter vascular- or immune cell activation in the context of dermal injury and fibrosis, we modified the standard model of intradermal bleomycin injection to include co-administration of platelet derived growth factor-BB (PDGF-BB), the ligand for PDGFRβ (Fig 1A)
Summary
Systemic sclerosis (SSc) is a complex multi-system autoimmune disease with three distinct pathologies that define the disease, namely: vasculopathy, aberrant immune activation, and tissue fibrosis [1]. Mice engineered to express a constitutively active form of PDGFRβ exhibit increased pericyte coverage in capillaries with evidence of aberrant production of interferon stimulatory genes (ISGs) and other inflammatory mediators by brain vascular cells [17] These mice do not develop tissue fibrosis, but they do exhibit extensive signs of perivascular inflammation and increased accumulation of myeloid cells in peripheral tissues. To investigate the roles of PDGF-BB and Type I IFNs in vasculopathy and aberrant immune cell activation in SSc, we developed a novel experimental model, which features PDGF-BB-dependent vascular activation, in combination with bleomycin-induced dermal injury and fibrosis We used this model to study the complex interactions that occur at the site of disease, and identify the mechanisms by which these interactions may influence SSc disease pathogenesis
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