Cho John S, Fang Terry C, Reynolds Taylor L, Sofia Daniel J, Hamann Stefan, Burkly Linda C
Immunology Research, Biogen, Cambridge, MA, United States of America.
Translational Sciences - Pathology, Biogen, Cambridge, MA, United States of America.
PLoS One. 2016 Sep 12;11(9):e0162758. doi: 10.1371/journal.pone.0162758. eCollection 2016.
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.
系统性硬化症（SSc）是一种慢性自身免疫性疾病，可导致皮肤广泛组织损伤，在晚期病例中还可累及内脏器官。血管病变、异常免疫激活和组织纤维化是已确定的该疾病的三个特征，其中血管病变和异常免疫是最早出现的事件。然而，这些过程之间的机制联系尚未建立。在此，我们发现血小板衍生生长因子-BB（PDGF-BB）/血小板衍生生长因子受体β（PDGFRβ）激活与博来霉素诱导的皮肤损伤相结合，可作为干扰素刺激基因（ISGs）早期异常表达和炎性单核细胞浸润的驱动因素。PDGFRβ激活与博来霉素诱导的皮肤损伤相结合导致皮肤厚度增加、血管密度增加、单核细胞/巨噬细胞浸润以及组织损伤加重。这些特征中的许多都依赖于IFNAR信号传导，并且在皮肤病变中发现产生干扰素-β（IFN-β）的单核细胞数量增加。综上所述，这些结果确定了PDGFRβ激活与I型干扰素驱动的血管维持和单核细胞/巨噬细胞募集之间的新联系，并为之前认为无关的SSc关键特征之间的联系提供了潜在解释。
