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HGNC Approved Gene Symbol: S100A8
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:153,390,032-153,422,583 (from NCBI)
Calprotectin, the heterodimeric protein complex composed of S100A8 and S100A9 (123886), 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.
Wilson et al. (1975) found a serum protein abnormality in both heterozygotes and homozygotes with cystic fibrosis (CF; 219700). Immunologic quantitation of the protein, called CF antigen, allowed the 3 genotypes to be distinguished (Manson and Brock, 1980; Bullock et al., 1982).
Van Heyningen et al. (1985) showed that a protein immunologically indistinguishable from CF antigen is present at high levels in granulocytes from normal and CF persons as well as in myeloid leukemia cells. They studied somatic cell hybrids between a mouse myeloid stem cell line and human myeloid leukemia cells and found that CFAg was expressed only when human chromosome 1 was present. The authors were inclined to think that the accumulated protein was itself the product of the CF gene and that it was altered so that it could not be processed normally; thus, the site of the mutation might be a region of a polypeptide chain that acts as a site for a specific proteolytic cleavage step.
Dorin et al. (1987) isolated cDNA clones for CFA from a library constructed with mRNA from chronic myeloid leukemia cells. The complete nucleotide sequence was obtained from the cDNA clone and by primary extension of mRNA. The amino acid sequence, as predicted from the nucleotide sequence, showed significant homology with intestinal and brain calcium-binding proteins. Dorin et al. (1987) concluded that abnormal accumulation of such a protein in CF should be investigated, since there is gathering evidence that the basic defect is in pathways controlling chloride channel activity (Welsh and Liedtke, 1986; Frizzell et al., 1986).
Wilkinson et al. (1988) produced monoclonal antibodies specifically recognizing CFAG. Immunoaffinity purification of CFAG from several sources showed 2 components: one of molecular weight 11,000 and one of molecular weight 14,000. Wilkinson et al. (1988) isolated cDNA clones corresponding to each protein. Since the major source of these proteins is neutrophil granulocytes, Wilkinson et al. (1988) suggested the names calgranulin A (CAGA) and B (CAGB; 123886). Both CAGA and CAGB show homology with the calcium-binding protein S100 (S100A1; 176940). Wilkinson et al. (1988) used the monoclonal antibodies to study tissue distribution of the 2 proteins. Strong expression was found in granulocytes and in a restricted subset of normal stratified squamous epithelium, including tongue, esophagus, and buccal cells. Lung, pancreas, and skin, sites where the cystic fibrosis defect is expressed, were not calgranulin-positive. A number of hyperproliferative neoplastic or frankly malignant epithelia were found to express the 2 proteins.
Using somatic cell hybrids containing rearranged human chromosomes, Dorin et al. (1987) localized the CFA gene to 1q12-q22.
Using probes for both subunits of the CF-associated antigen, isolated from a chronic myeloid leukemia-derived cDNA library, van Heyningen et al. (1989) and Dorin et al. (1990) confirmed the assignment of CFAG (CAGA) to 1q12-q21 and showed that CAGB cosegregates with it in a panel of somatic cell hybrids.
Gross (2014) mapped the S100A8 gene to chromosome 1q21.3 based on an alignment of the S100A8 sequence (GenBank BC005928) with the genomic sequence (GRCh38).
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.
Calprotectin is a protein complex consisting of S100A8 and S100A9. 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.
Vogl et al. (2007) demonstrated that mice lacking Mrp8-Mrp14 (123886) 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. 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.
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 a major calcium- and zinc-binding protein in the cytosol of neutrophils, monocytes, and keratinocytes. Although serum concentrations of calprotectin are raised in many inflammatory conditions, they are generally lower than 10 mg/L. Sampson et al. (2002) reported greatly elevated serum concentrations in 5 patients with hyperzincemia and hypercalprotectinemia (194470), a seemingly novel disorder of zinc metabolism. All 5 patients presented with recurrent infections, hepatosplenomegaly, anemia, and evidence of systemic inflammation. Cutaneous inflammation was present in 3, and 3 presented in infancy with severe growth failure. As no structural defects in the S100A8 or S100A9 subunits of calprotectin were detected, Sampson et al. (2002) suggested that the hypercalprotectinemia was caused by a defect in its metabolism.
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 being closest to the telomere and S100A9 being closest to the centromere. In the new nomenclature, CAGA became S100A8. Schafer et al. (1995) commented that S100A8 had been given 9 different names by groups who had independently studied the same protein.
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 supported 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.
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