The Role of CXCL4 in Systemic Sclerosis: DAMP, Auto-Antigen and Biomarker

Systemic sclerosis (SSc) is an autoimmune disease characterized by specific autoantibodies, vasculopathy and fibrosis of the skin and internal organs. In SSc, chronic activation of the immune system is largely sustained by endogenous inflammatory mediators that act as damage-associated molecular patterns (DAMPs), which activate Toll-like receptors (TLRs). Major autoantigens are nucleic acids or molecules that are able to bind nucleic acids. It is important to identify solid and predictive biomarkers of both disease activity and disease subtype. CXCL4 has been regarded as a new biomarker for early SSc in recent years, and here, we discuss its modulation over the course of a disease and after pharmacological interventions. Moreover, we provide evidence that CXCL4, in addition to being a biomarker of SSc subtypes and a prognostic marker of disease severity, has a dual pathogenic role in SSc: on the one hand, in complex with self-nucleic acids, CXCL4 acts as a DAMP for IFN-I and pro-inflammatory cytokines' release by innate immune cells (such as dendritic cells); on the other hand, CXCL4 is a target of both antibodies and T cells, functioning as an autoantigen. CXCL4 is certainly an interesting molecule in inflammation and autoimmunity, not only in SSc, and it may also be considered as a therapy target.