S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) orcalgranulin B is aprotein that in humans is encoded by theS100A9gene.[5]
S100A9 is a member of theS100 family of proteins containing 2EF hand calcium-binding motifs. S100 proteins are localized in thecytoplasm and/ornucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in the inhibition ofcasein kinase.[5]
MRP14 complexes with MRP-8 (S100A8), another member of the S100 family of calcium-modulated proteins; together, MRP8 and MRP14 regulate myeloid cell function by binding to Toll-like receptor 4 (TLR4)[6][7] and the receptor for advanced glycation end products.[8]
Intracellular S100A9 alters mitochondrial homeostasis withinneutrophils. As a result, neutrophils lacking S100A9 produce higher levels of mitochondrial superoxide and undergo elevated levels ofsuicidal NETosis in response to bacterial pathogens.[9] Furthermore, S100A9-deficient mice are protected from systemicStaphylococcus aureus infections with lower bacterial burdens in the heart, which suggests an organ-specific function for S100A9.[9][10]
Altered expression of the S100A9 protein is associated with the diseasecystic fibrosis.[5]
MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promotingleukocyte recruitment.[11]
MRP-8/14 also regulates vascular insults by controllingneutrophil andmacrophage accumulation,macrophagecytokine production, andSMC proliferation. The above study has shown therefore the deficiency of MRP-8 and MRP-14 reduces neutrophil- and monocyte-dependent vascular inflammation and attenuates the severity of diverse vascular injury responses in vivo. MRP-8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention.[12] Also, the platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before ST-segment-elevation myocardial infarction, (STEMI), and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.[13]
S100A9 (myeloid-related protein 14, MRP 14 or calgranulin B) has been implicated in the abnormal differentiation ofmyeloid cells in thestroma of cancer, and to leukemia progression.[14][15] This contributes to creating an overall immunosuppressive microenvironment that may contribute to the inability of a protective or therapeutic cellular immune response to be generated by the tumor-bearing host. Outside of malignancy, S100A9 in association with its dimerization partner,S100A8 (MRP8 or calgranulin A) signals for lymphocyte recruitment in sites of inflammation.[16] S100A9/A8 (synonyma: Calgranulin A/B; Calprotectin) are also regarded as marker proteins for a number of inflammatory diseases in humans, especially in rheumatoid arthritis andinflammatory bowel disease (IBD).
Myeloid-related protein (MRP)-8 is an inflammatory protein found in several mucosal secretions. In cervico-vaginal secretions MRP-8 can stimulate HIV production;[17] and thus might be involved in sexual transmission of HIV, as well as other sexually transmitted diseases (STD). In Vitro studies have shown that HIV-inducing of recombinant MRP-8 can increase HIV expression by up to 40-fold.[17]
A S100A9knockout mouse has (a mouse mutant, that is deficient of S100A9) been constructed. This mouse is fertile, viable and healthy. However, expression of S100A8 protein, the dimerization partner of S100A9, is also absent in these mice in differentiated myeloid cells.[18] This mouse line has been used to study the role of S100A9 and S100A8 in a number of experimental inflammatory conditions.
^Hiratsuka S, Watanabe A, Aburatani H, Maru Y (December 2006). "Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis".Nat. Cell Biol.8 (12):1369–75.doi:10.1038/ncb1507.PMID17128264.S2CID36876191.
Schäfer BW, Heizmann CW (1996). "The S100 family of EF-hand calcium-binding proteins: functions and pathology".Trends Biochem. Sci.21 (4):134–40.doi:10.1016/S0968-0004(96)80167-8.PMID8701470.
Nacken W, Roth J, Sorg C, Kerkhoff C (2003). "S100A9/S100A8: Myeloid representatives of the S100 protein family as prominent players in innate immunity".Microsc. Res. Tech.60 (6):569–80.doi:10.1002/jemt.10299.PMID12645005.S2CID10145841.
Rasmussen HH, van Damme J, Puype M, et al. (1993). "Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes".Electrophoresis.13 (12):960–9.doi:10.1002/elps.11501301199.PMID1286667.S2CID41855774.
Longbottom D, Sallenave JM, van Heyningen V (1992). "Subunit structure of calgranulins A and B obtained from sputum, plasma, granulocytes and cultured epithelial cells".Biochim. Biophys. Acta.1120 (2):215–22.doi:10.1016/0167-4838(92)90273-G.PMID1562590.
Dorin JR, Emslie E, van Heyningen V (1991). "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 (3):420–6.doi:10.1016/0888-7543(90)90027-R.PMID2149559.
Schäfer BW, Wicki R, Engelkamp D, et al. (1995). "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 (3):638–43.doi:10.1016/0888-7543(95)80005-7.PMID7759097.
Miyasaki KT, Bodeau AL, Murthy AR, Lehrer RI (1993). "In vitro antimicrobial activity of the human neutrophil cytosolic S-100 protein complex, calprotectin, against Capnocytophaga sputigena".J. Dent. Res.72 (2):517–23.doi:10.1177/00220345930720020801.PMID8423249.S2CID8311930.
