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HGNC Approved Gene Symbol: S100A9
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:153,357,854-153,361,023 (from NCBI)
Calprotectin, the heterodimeric protein complex composed of S100A8 (123885) and S100A9, is a major calcium- and zinc-binding protein in the cytosol of neutrophils, monocytes, and keratinocytes (Sampson et al., 2002). Vogl et al. (2007) noted that complexes of S100A8 and S100A9 are the physiologically relevant forms of these proteins.
See 123885 for a description of calgranulin A (CAGA) and calgranulin B (CAGB), which have molecular weights 11,000 and 14,000, respectively, and together represent the cystic fibrosis antigen (CFAG). They are coded by separate genes. Odink et al. (1987) identified and cloned the calgranulin B gene, CAGB, also known as MRP14.
Gross (2014) mapped the S100A9 gene to chromosome 1q21.3 based on an alignment of the S100A9 sequence (GenBank AF237581) with the genomic sequence (GRCh38).
By study of DNA from a panel of somatic cell hybrids, van Heyningen et al. (1989) and Dorin et al. (1990) showed that the CAGB gene cosegregates with CAGA (S100A8; 123885) in somatic cell hybrids and that both are closely situated to calcyclin (S100A6; 114110) and calcium placental protein (S100A4; 114210).
Psoriasis (see 177900) is an inflammatory skin disorder characterized by keratinocyte hyperproliferation and altered differentiation. Linkage analyses have identified at least 7 distinct disease susceptibility regions. PSORS4 (603935) maps to chromosome 1q21, within the epidermal differentiation complex (EDC; see 152445), a cluster that contains 13 genes encoding S100 calcium-binding proteins. Semprini et al. (2002) analyzed S100 gene expression in psoriatic individuals from 2 large pedigrees characterized by linkage studies, 1 linked and 1 unlinked to the 1q21 locus. The analyses demonstrated that only the 1q21-linked family had upregulation of S100A8, S100A9, and, to a lesser extent, S100A7 (600353) and S100A12 (603112). Later studies confirmed S100A8/S100A9-specific overexpression in 1q-linked pedigrees.
Vogl et al. (2007) demonstrated that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein-88 (MYD88; 602170) and activation of interleukin-1 receptor-associated kinase-1 (IRAK1; 300283) and nuclear factor-kappa-B (NFKB; see 164011), resulting in elevated expression of tumor necrosis factor-alpha (TNF-alpha; 191160). Using phagocytes expressing a nonfunctional Toll-like receptor-4 (TLR4; 603030), HEK293 cells transfected with TLR4, CD14 (158120), and MD2 (LY96; 605243), and by surface plasmon resonance studies in vitro, Vogl et al. (2007) demonstrated that MRP8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. The data demonstrated that MRP8 is the active component of the complex, while MRP14 seems to regulate MRP8 function. Vogl et al. (2007) concluded that MRP8-MRP14 complexes are novel inflammatory components that amplify phagocyte activation during sepsis upstream of TNF-alpha-dependent effects.
Corbin et al. (2008) found that neutrophil-derived calprotectin inhibited growth of Staphylococcus aureus in abscesses through chelation of Mn(2+) and Zn(2+), an activity that resulted in reprogramming of the bacterial transcriptome. Abscesses of mice lacking calprotectin had enhanced levels of metals and increased staphylococcal proliferation. Corbin et al. (2008) concluded that calprotectin is a critical factor in the innate immune response to infection and that metal chelation is a mechanism for inhibiting microbial growth inside abscessed tissue.
Using a mouse model of autoimmunity, Loser et al. (2010) showed that production of the damage-associated molecular pattern (DAMP) molecules Mrp8 and Mrp14 was essential for induction of autoreactive Cd8 (see 186910)-positive T cells and development of systemic autoimmunity. FACS analysis demonstrated that this effect of Mrp8 and Mrp14 was associated with Tlr4 signaling and increased Il17 (603149) expression. Immunohistochemical analysis revealed upregulated MRP8 and MRP14 expression in human cutaneous lupus erythematosus (see 152700) lesions, and MRP8 and MRP14 were detectable in sera from individuals with active disease. IL17 was upregulated in CD8-positive T cells from individuals with lupus when stimulated with MRP8 and MRP14, suggesting that MRP8 and MRP14 have a key role in the development of autoreactive lymphocytes during autoimmune disease. Loser et al. (2010) concluded that there is a link between the local expression of DAMP molecules and systemic autoimmunity.
Using proteomic analysis on human psoriatic epidermis, Schonthaler et al. (2013) identified S100A8 and S100A9, followed by complement component-3 (C3; 120700), as the most upregulated proteins specifically expressed in lesional psoriatic skin. Confocal microscopy of human primary keratinocytes treated with TPA (PLAT; 173370) demonstrated a strong increase in nuclear as opposed to cytoplasmic expression of S100A9. Chromatin immunoprecipitation analysis on human keratinocytes suggested binding of S100A9 to the C3 promoter. Schonthaler et al. (2013) concluded that S100A8/S100A9 has a nuclear function in the regulation of C3.
By RT-PCR and immunohistochemical analysis, Gopal et al. (2013) demonstrated that rhesus macaques and humans with active tuberculosis (TB; see 607948) compared with latent TB infection had increased levels of S100A8 and neutrophils expressing S100A8. Additionally, serum levels of S100A8/S100A9, IP10 (CXCL10; 147310), and the neutrophil and keratinocyte chemoattractant KC (CXCL1; 155730) were increased in active TB compared with latent TB infection. Gopal et al. (2013) proposed that serum levels of S100A8/S100A9, along with chemokines such as KC, can be used as surrogate markers of lung inflammation during TB and can predict the development of active TB in patients with latent TB infection in TB-endemic, high-risk populations.
By stimulating normal human bronchial epithelial cells and human lung carcinoma cells with S100A8, S100A9, or S100A12, Kang et al. (2015) observed dose-dependent induction of MUC5AC (158373) expression. A TLR4 inhibitor largely blocked MUC5AC expression by all 3 S100 proteins, whereas neutralization of RAGE (AGER; 600214) inhibited only S100A12-mediated production of MUC5AC. S100 protein-mediated MUC5AC production was inhibited by pharmacologic agents that blocked signaling molecules involved in MUC5AC expression, such as MAP kinases (e.g., MAPK3; 601795), NFKB, and EGFR (131550). S100A8, S100A9, and S100A12 equally elicited phosphorylation of ERK and nuclear translocation of NFKB/degradation of cytosolic I-kappa-B (see 164008) through TLR4. S100A12, however, preferentially activated MAPK3 pathways rather than the NFKB pathway through RAGE. Kang et al. (2015) concluded that S100 proteins induce MUC5AC production in airway epithelial cells, suggesting that they serve as key mediators linking neutrophil-dominant airway inflammation to mucin hyperproduction.
Calprotectin, the complex of S100A8 and S100A9, is the major calcium- and zinc-binding protein of phagocytes. Sampson et al. (2002) reported 5 cases of hypercalprotectinemia (194470), a syndrome characterized by hyperzincemia associated with excessively high plasma concentrations of calprotectin. All patients presented with recurrent infections, hepatosplenomegaly, anemia, and evidence of systemic inflammation; 2 patients were mother and son. Sampson et al. (2002) concluded that there was probably no primary defect in S100A8 or S100A9, but that the metabolism of calprotectin was defective.
Schafer et al. (1995) isolated a YAC from 1q21 on which 9 different genes coding for S100 calcium-binding proteins could be localized. The clustered organization of S100 genes allowed introduction of a new logical nomenclature based on their physical arrangement on the chromosome with S100A1 (176940) being closest to the telomere and S100A9 being closest to the centromere. In the new nomenclature, CAGB became S100A9.
Zenz et al. (2005) showed that inducible epidermal deletion of JunB (165161) and its functional companion c-Jun (165160) in adult mice leads within 2 weeks to a phenotype resembling the histologic and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions required T and B cells and signaling through tumor necrosis factor receptor-1 (TNFR1; 191190). Prior to the disease onset, the chemotactic proteins S100A8 and S100A9, which map to the psoriasis susceptibility region PSORS4, were strongly induced in mutant keratinocytes in vivo and in vitro. Zenz et al. (2005) proposed that the abrogation of JunB/activator protein-1 (AP1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis, thereby contributing to the phenotypic changes observed in psoriasis. Thus, their data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.
Schonthaler et al. (2013) deleted S100a9 in the Jun/JunB double-knockout (DKO) mouse model of psoriasis. The authors found an absence of scaly plaques on the ears and tails in S100a9 -/- DKO mice, as well as decreased amounts of C3. Inhibition of C3 in DKO mice also strongly reduced inflammatory skin disease. Chromatin immunoprecipitation analysis using DKO cells and S100a9 DKO -/- cells as controls demonstrated binding of S100a9 to the C3 promoter region. Schonthaler et al. (2013) concluded that S100A8/S100A9 regulates C3 at the nuclear level.
Using 'diversity outbred' (DO) mice, Gopal et al. (2013) observed different lung inflammatory responses and susceptibility to infection with Mycobacterium tuberculosis (Mtb). Lower Mtb burdens were associated with well-organized B-lymphoid follicles and elevated Ifng (147570). Mice with increased pulmonary inflammation harbored more S100a8-expressing neutrophils and showed increased Cxcl1, Il17, and lung S100a8/S100a9 expression. Treatment of Mtb-infected wildtype mice with anti-Ifng resulted in increased accumulation of S100a8-expressing neutrophils and exacerbation of inflammation. In contrast, treatment of Mtb-infected S100a9 -/- mice, which also do not express S100a8, with anti-Ifng resulted in loss of lung inflammation and neutrophil accumulation. Gopal et al. (2013) concluded that IL17 overexpression, through an S100A8/S100A9-dependent pathway, mediates exacerbated neutrophil recruitment and lung inflammation during TB.
Corbin, B. D., Seeley, E. H., Raab, A., Feldmann, J., Miller, M. R., Torres, V. J., Anderson, K. L., Dattilo, B. M., Dunman, P. M., Gerads, R., Caprioli, R. M., Nacken, W., Chazin, W. J., Skaar, E. P. Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319: 962-965, 2008. [PubMed: 18276893] [Full Text: https://doi.org/10.1126/science.1152449]
Dorin, J. R., Emslie, E., van Heyningen, V. Related calcium-binding proteins map to the same subregion of chromosome 1q and to an extended region of synteny on mouse chromosome 3. Genomics 8: 420-426, 1990. [PubMed: 2149559] [Full Text: https://doi.org/10.1016/0888-7543(90)90027-r]
Gopal, R., Monin, L., Torres, D., Slight, S., Mehra, S., McKenna, K. C., Fallert Junecko, B. A., Reinhart, T. A., Kolls, J., Baez-Saldana, R., Cruz-Lagunas, A., Rodriguez-Reyna, T. S., and 15 others. S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am. J. Respir. Crit. Care Med. 188: 1137-1146, 2013. [PubMed: 24047412] [Full Text: https://doi.org/10.1164/rccm.201304-0803OC]
Gross, M. B. Personal Communication. Baltimore, Md. 10/21/2014.
Kang, J. H., Hwang, S. M., Chung, I. Y. S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC5AC via extracellular signal-regulated kinase and nuclear factor-kappa-B pathways. Immunology 144: 79-90, 2015. [PubMed: 24975020] [Full Text: https://doi.org/10.1111/imm.12352]
Loser, K., Vogl, T., Voskort, M., Lueken, A., Kupas, V., Nacken, W., Klenner, L., Kuhn, A., Foell, D., Sorokin, L., Luger, T. A., Roth, J., Beissert, S. The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nature Med. 16: 713-717, 2010. [PubMed: 20473308] [Full Text: https://doi.org/10.1038/nm.2150]
Odink, K., Cerletti, N., Bruggen, J., Clerc, R. G., Tarcsay, L., Zwadlo, G., Gerhards, G., Schlegel, R., Sorg, C. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 330: 80-82, 1987. [PubMed: 3313057] [Full Text: https://doi.org/10.1038/330080a0]
Sampson, B., Fagerhol, M. K., Sunderkotter, C., Golden, B. E., Richmond, P., Klein, N., Kovar, I. Z., Beattie, J. H., Wolska-Kusnierz, B., Saito, Y., Roth, J. Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism. Lancet 360: 1742-1745, 2002. [PubMed: 12480428] [Full Text: https://doi.org/10.1016/S0140-6736(02)11683-7]
Schafer, B. W., Wicki, R., Engelkamp, D., Mattei, M.-G., Heizmann, C. W. Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome 1q21: rationale for a new nomenclature of the S100 calcium-binding protein family. Genomics 25: 638-643, 1995. [PubMed: 7759097] [Full Text: https://doi.org/10.1016/0888-7543(95)80005-7]
Schonthaler, H. B., Guinea-Viniegra, J., Wculek, S. K., Ruppen, I., Ximenez-Embun, P., Guio-Carrion, A., Navarro, R., Hogg, N., Ashman, K., Wagner, E. F. S100A8-S100A9 protein complex mediates psoriasis by regulating the expression of complement factor C3. Immunity 39: 1171-1181, 2013. [PubMed: 24332034] [Full Text: https://doi.org/10.1016/j.immuni.2013.11.011]
Semprini, S., Capon, F., Tacconelli, A., Giardina, E., Orecchia, A., Mingarelli, R., Gobello, T., Zambruno, G., Botta, A., Fabrizi, G., Novelli, G. Evidence for differential S100 gene over-expression in psoriatic patients from genetically heterogeneous pedigrees. Hum. Genet. 111: 310-313, 2002. [PubMed: 12384771] [Full Text: https://doi.org/10.1007/s00439-002-0812-5]
van Heyningen, V., Emslie, E., Dorin, J. R. Related calcium binding proteins map to the same sub-region of chromosome 1q and to an extended region of synteny on mouse chromosome 3. (Abstract) Cytogenet. Cell Genet. 51: 1095 only, 1989.
Vogl, T., Tenbrock, K., Ludwig, S., Leukert, N., Ehrhardt, C., van Zoelen, M. A. D., Nacken, W., Foell, D., van der Poll, T., Sorg, C., Roth, J. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nature Med. 13: 1042-1049, 2007. [PubMed: 17767165] [Full Text: https://doi.org/10.1038/nm1638]
Zenz, R., Eferl, R., Kenner, L., Florin, L., Hummerich, L., Mehic, D., Scheuch, H., Angel, P., Tschachler, E., Wagner, E. F. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437: 369-375, 2005. Note: Erratum: Nature 440: 708 only, 2006. [PubMed: 16163348] [Full Text: https://doi.org/10.1038/nature03963]