EXPRESS: Calprotectin in Systemic Sclerosis: Pathogenic Roles and Emerging Biomarker Potential

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by microvascular injury, immune dysregulation, and progressive fibrosis affecting the skin and multiple internal organs. Growing evidence suggests that calprotectin, a heterodimeric calcium-binding protein composed of S100A8 and S100A9, may contribute to the inflammatory processes involved in SSc pathogenesis. Increased calprotectin levels have been reported in multiple biological compartments of SSc patients, including bronchoalveolar lavage fluid, plasma, feces, skin, and saliva, and have been associated with systemic inflammatory activity and specific organ manifestations. Mechanistically, calprotectin functions as a damage-associated molecular pattern and may amplify inflammatory signaling through Toll-like receptor 4 (TLR4) and receptor for advanced glycation end-products (RAGE) pathways, potentially contributing to endothelial dysfunction, immune activation, and fibroblast-mediated fibrotic responses. Current evidence indicates that calprotectin may be involved in key clinical manifestations of SSc, particularly interstitial lung disease and gastrointestinal involvement, although its precise pathogenic role and clinical significance remain incompletely defined. This review summarizes current research on the biological characteristics of calprotectin in SSc, its distribution across different biological sources, and its potential value as a non-invasive biomarker candidate for assessing disease activity, organ involvement, and treatment response, while highlighting current limitations and future research directions.