{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nS100A8 is a small calcium‐binding protein highly expressed in neutrophils and monocytes that plays a pivotal role in innate immunity. In these cells, S100A8 (often in heterodimeric association with S100A9) promotes neutrophil chemotaxis, induces the shedding of adhesion molecules such as L‐selectin, and up‐regulates integrins necessary for firm adhesion and transendothelial migration. In addition, S100A8/S100A9 modulates cytoskeletal dynamics via regulation of tubulin polymerization, thereby enabling rapid cell locomotion during inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its function in cell migration, S100A8—usually acting as part of the S100A8/A9 complex, known as calprotectin—is critical for host defense. It sequesters essential transition metals (Mn²⁺ and Zn²⁺) to restrict pathogen growth, and it also facilitates NADPH oxidase activation by binding components such as p67^phox and Rac, thereby promoting reactive oxygen species generation. Moreover, posttranslational S‐nitrosylation of S100A8 can modulate nitric oxide transport and dampen mast cell activation, contributing to the control of local inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nExtracellularly, S100A8/A9 acts as a damage‐associated molecular pattern that engages receptors—including the receptor for advanced glycation end products (RAGE) and Toll‑like receptor 4 (TLR4)—to amplify inflammatory signaling. Binding to these receptors leads to activation of NF‑κB and MAP kinase pathways and subsequent production of proinflammatory cytokines, chemokines, and other mediators. This cascade not only reinforces local inflammatory responses in conditions such as rheumatoid arthritis, systemic lupus erythematosus, and juvenile idiopathic arthritis but also contributes to broader immune dysregulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the tumor microenvironment, S100A8 contributes to cancer progression by engaging RAGE‐mediated signaling that activates NF‑κB and MAPK pathways, leading to the up‐regulation of genes involved in cell proliferation, migration, and invasion. S100A8/A9 produced by myeloid‐derived suppressor cells and tumor‐infiltrating inflammatory cells has been implicated in promoting metastasis and in serving as a diagnostic marker in various malignancies—including colon, prostate, and breast cancers—by correlating with aggressive disease phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nS100A8 also plays diverse roles in non‐malignant conditions. In vascular biology, its actions on endothelial cells can promote a prothrombotic and inflammatory state and, in atherosclerotic lesions, this protein complex has been linked to redox and calcium‐dependent processes that may favor calcification. In musculoskeletal conditions such as osteoarthritis and inflammatory bowel disease, high levels of calprotectin serve as both active drivers of tissue catabolism and as sensitive biomarkers. Its calcium‐ and zinc‐dependent oligomerization is critical for regulating microtubule dynamics and cell adhesion, while S100A8/A9 released into amniotic fluid or airway secretions is associated with antimicrobial responses, mucin production, and skin inflammation seen in psoriasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, emerging evidence highlights roles for S100A8 in hematologic regulation and in severe viral infections. Genetic studies have linked aberrant expression of S100A8 to defective erythroid differentiation observed in myelodysplastic syndromes, while markedly elevated serum levels of calprotectin have been associated with hyperinflammatory states in conditions such as COVID‑19."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carle Ryckman, Karen Vandal, Pascal Rouleau, et al. 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