LAUSR

Systemic Sclerosis (SSc) or Scleroderma is a complex and puzzling disease having an incidence of 1– 2 cases per 100,000. In SSc, inflammation leads to organ failure due to severe fibrosis of the skin and internal organs. At late stages, this disease is characterized by a profound decline in the quality of life and premature death (1). The Research Topic “Etiopathogenesis of Systemic Sclerosis: An Update” is aiming to explore three major features of SSc: vascular injury, fibrosis, and immune dysregulation. Here, we summarize the novel insights reported in this Topic with a list of references to further exploit the given issues. Apostolidis et al. identify genes linked to vascular injury in SSc by scRNAseq. Among several genes, they found Apelin Receptor (APLNR) and Heparan Sulfate Proteoglycan 2 (HSPG2), not yet associated to SSc pathogenesis but of great interest as they have been reported to sustain vascular dysfunction and fibrosis in different settings (2). These data provide the ground to characterize new biomarkers of vascular injury and, possibly, therapeutic targets. Svegliati et al. define the role of the Antiplateletderived growth factor (PDGF) autoantibodies in vascular injury. The authors analyze the expression of distinct functional markers of smooth muscle cells (SMC) from human pulmonary arteries (HPASMC) exposed in vitro to anti-PDGFR autoantibodies from SSc patients. They show that PDGFR autoantibodies activate SMC and may contribute to the development of SSc vascular lesions, therefore suggesting that a downregulation of B cell response could modify disease development (3). Napolitano et al. show that N-formyl peptide receptors (FPRs) can induce Reactive Oxygen Species (ROS) generation in fibroblasts through the interaction with the urokinase-type plasminogen activator/uPA receptor (uPA/uPAR) system, activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and alteration of the redox state observed in SSc. Napolitano’s data indicate novel therapeutic strategies in SSc, through the use of small molecules to impair FPRs functional interaction with uPAR and their signal (4). Dolcino et al. suggest the presence of modulated genes and miRNAs playing a predisposing role in the development of malignancies in SSc. Genetic and epigenetic features shared by SSc and cancer shed new light on the pathogenesis of the disease and support the idea that immune activation against a tumor may have a central role in the initiation and progression of SSc, as also indicated by the presence or development of malignancies associated with particular autoantibodies (5). Xiong et al. show that in a murine model of SSc, Sclerodermatous Graft Versus Host Disease (sclGvHD), daily stretching produced a measurable beneficial on reducing skin thickness and improved mobility during the fibrotic phase of the model. Of note, stretching reduced mRNA expression of C-C Motif