High mobility group motif proteins’ role in fibrosis, inflammation, and vascular injury in systemic sclerosis

Systemic Sclerosis (SSc) is an idiopathic systemic autoimmune disease characterized by progressive cutaneous and systemic fibrosis, severe vasculopathy, and multiple humoral and cellular immunological alterations. The pathogenesis of SSc is highly complex and remains incompletely elucidated. The fibrotic process is a crucial component of SSc and is responsible for organ failure and high mortality. Although an increasing understanding of the fibrotic process has enabled the clinical development of antifibrotic therapeutic agents, these agents have limited clinical efficacy. Recently, the potential role of a group of transcription factors containing a High Mobility Group (HMG) motif, in the development and pathological manifestations of SSc has been postulated. HMG proteins (notably HMGB1 and SOX9) act as profibrotic and proinflammatory transcription factors; however, HMG proteins can also function as damage-associated molecular patterns, amplifying Toll-like receptors and RAGE signaling, promoting endothelial activation, leukocyte recruitment, and stimulating the production of profibrotic cytokines. This convergent role of HMG proteins across various aspects of SSc pathogenesis, including immune dysregulation, vasculopathy, and fibrosis, makes them among the most attractive novel regulators and a desirable therapeutic target for SSc. Here, we review the recent evidence on the role of HMG proteins in SSc pathogenesis and explore the potential role of inhibiting their function.