Protein S100-A9

Also known as: Calgranulin-B, Calprotectin L1H subunit, Leukocyte L1 complex heavy chain, Migration inhibitory factor-related protein 14, S100 calcium-binding protein A9, S100A9, P06702

**Mechanism of Action** Protein S100-A9 (calgranulin-B) is a member of the S100 family of calcium-binding proteins, predominantly expressed in neutrophils, monocytes, and epithelial cells. It forms heterodimers with S100-A8 (calprotectin) and, upon calcium binding, undergoes conformational changes that enable interaction with toll-like receptor 4 (TLR4) and receptor for advanced glycation end-products (RAGE). This activates NF-κB and MAPK signaling pathways, promoting pro-inflammatory cytokine release (e.g., IL-6, TNF-α) and chemotaxis. S100-A9 also sequesters zinc and manganese, exerting antimicrobial effects by depriving pathogens of essential metals. **Key Research Findings** Elevated S100-A9 levels are consistently observed in inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, and sepsis, where it correlates with disease activity. In cancer, S100-A9 promotes tumor progression via myeloid-derived suppressor cell (MDSC) recruitment and angiogenesis. Preclinical studies show that S100-A9 knockout mice exhibit reduced inflammation and tumor growth. Its role in sterile inflammation (e.g., atherosclerosis, obesity) is also under investigation, with 44 PubMed-indexed studies highlighting its potential as a biomarker and therapeutic target. **Clinical Relevance** S100-A9 is a validated biomarker for monitoring inflammatory disease activity (e.g., fecal calprotectin in IBD). Therapeutic strategies targeting S100-A9 include neutralizing antibodies (e.g., anti-S100A9 in phase II trials for psoriasis) and small-molecule inhibitors of TLR4/RAGE signaling. However, its dual role in host defense and chronic inflammation necessitates careful modulation. Further clinical validation is required for cancer and autoimmune indications. For research purposes only — not medical advice.

Key data

Mechanism of action

S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response (PubMed:12626582, PubMed:15331440, PubMed:16258195, PubMed:19122197, PubMed:20103766, PubMed:21325622, PubMed:8423249). It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism (PubMed:12626582, PubMed:15331440, PubMed:20103766). Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions (PubMed:16258195, PubMed:19122197, PubMed:8423249). The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase (PubMed:15331440, PubMed:21325622). Also participates in regulatory T-cell differentiation together with CD69 (PubMed:26296369). Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX (PubMed:15642721, PubMed:22808130). The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities (PubMed:19534726, PubMed:8423249). Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration (PubMed:15598812, PubMed:21487906). Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER) (PubMed:19402754). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade (PubMed:19402754, PubMed:22804476). Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth (PubMed:19087201). Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3 (PubMed:19935772). Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK (PubMed:22363402). Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants (PubMed:21912088, PubMed:22489132). Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread (PubMed:16258195). Has transnitrosylase activity; in oxidatively-modified low-densitity lipoprotein (LDL(ox))-induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3 (PubMed:25417112). The iNOS-S100A8/A9 transnitrosylase complex is proposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif (PubMed:25417112)

Research & studies

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