Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities

Systemic sclerosis (SSc) is a complex disease characterized by early microvascular abnormalities, immune dys-regulation and chronic inflammation, and subsequent fibrosis of the skin and internal organs. Excessive fibrosis, distinguishing hallmark of SSc, is the end result of a complex series of interlinked vascular injury and immune activation, and represents a maladaptive repair process. Activated vascular, epithelial, and immune cells generate pro-fibrotic cytokines, chemokines, growth factors, lipid mediators, autoantibodies, and reactive oxygen species. These paracrine and autocrine cues in turn induce activation, differentiation, and survival of mesenchymal cells, ensuing tissue fibrosis through increased collagen synthesis, matrix deposition, tissue rigidity and remodeling, and vascular rarefaction. This review features recent insights of the pathogenic process of SSc, highlighting three major characteristics of SSc, microvasculopathy, excessive fibrosis, and immune dysregulation, and sheds new light on the understanding of molecular and cellular mechanisms contributing to the pathogenesis of SSc and providing novel avenues for targeted therapies.