MRP8 (S100A8) and MRP14 (S100A9) in inflammatory diseases.
The innate immunsystem comprises the first line of defense against invading pathogens and is involved in many inflammatory diseases either by amplifying or attenuating inflammatory responses. Monocytes and neutrophils are the major players herein expressing a variety of pro-inflammatory proteins.MRP8 (myeloid related protein, S100A8) and MRP14 (S100A9) are expressed by early recruited monocytes and granulocytes. They are the most abundant calcium-binding proteins in phagocytes. Release of these proteins correlates with inflammatory activation of phagocytes. We have developed a sensitive and specific ELISA to quantify MRP8/MRP14. Serum concentrations of these proteins correlate well with local inflammation. They are reliable serum markers in various inflammatory disorders, e. g. rheumatoid arthritis, inflammatory bowel disease, inflammatory lung disease, SLE, vasculitis and dermatomyositis. Both proteins are also discussed as prognostic markers during cardiovascular disease. In addition to the continuous evaluation of the diagnostic capacities of MRP8/MRP14 serum analyses our group investigates pro-inflammatory functions of MRP8/MRP14.The complex of MRP8/MRP14 interacts with structures of the cytoskeleton and is secreted by activated phagocytes. We have established the first MRP14 -/- mouse in our lab. Targeted deletion of MRP14 in mice revealed a role in cytoskeletal metabolism as well as pro-inflammatory effects of these molecules via activation of Toll-Like-Receptor-4 which point to a prominent role in host defense and inflammation. Furthermore, over-expression of these proteins is associated with a chronic inflammatory disorder.Using site-directed mutagenesis, microarray gene expression analysis and several biochemical and functional assays we precede our work to define the exact role of these S100-proteins during inflammatory activation of phagocytes.
Research papers of our group:
Björk P, Björk A, Vogl T, Stenström M, Liberg D, Olsson A, Roth J, Ivars F, Leanderson T. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides.
PLoS Biol. 2009; 7(4):e97.
Frosch M, Ahlmann M, Vogl T, Wittkowski H, Wulffraat N, Foell D, Roth J. The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis.
Arthritis Rheum. 2009;60(3):883-91.
Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein.
J Exp Med. 2008; 205(10):2235-49.
Corbin BD, Seeley EH, Raab A, Feldmann J, Miller MR, Torres VJ, Anderson KL, Dattilo BM, Dunman PM, Gerads R, Caprioli RM, Nacken W, Chazin WJ, Skaar EP. Metal chelation and inhibition of bacterial growth in tissue abscesses.
Science. 2008; 319(5865):962-5.
Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, 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.
Nat Med. 2007; 13(9):1042-9.
Viemann D, Barczyk K, Vogl T, Fischer U, Sunderkötter C, Schulze-Osthoff K, Roth J. MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program.
Blood. 2007; 109(6):2453-60.
Viemann D, Strey A, Janning A, Jurk K, Klimmek K, Vogl T, Hirono K, Ichida F, Foell D, Kehrel B, Gerke V, Sorg C, Roth J. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells.
Blood. 2005; 105(7):2955-62.
Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, Foell D, Gerke V, Manitz MP, Nacken W, Werner S, Sorg C, Roth J. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes.
Blood. 2004; 104(13):4260-8.
Sampson B, Fagerhol MK, Sunderkötter C, Golden BE, Richmond P, Klein N, Kovar IZ, Beattie JH, Wolska-Kusnierz B, Saito Y, Roth J. Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism.
Lancet. 2002; 360(9347):1742-5.
Ehrchen JM, Sunderkötter C, Foell D, Vogl T, Roth J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer.
J Leukoc Biol. 2009 (in press).
Foell D, Wittkowski H, Roth J. Mechanisms of disease: a 'DAMP' view of inflammatory arthritis.
Nat Clin Pract Rheumatol. 2007; 3(7):382-90.
Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules.
J Leukoc Biol. 2007; 81(1):28-37.
Roth J, Vogl T, Sorg C, Sunderkötter C. Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules.
Trends Immunol. 2003; 24(4):155-8.
Foell D, Roth J. Proinflammatory S100 proteins in arthritis and autoimmune disease.
Arthritis Rheum. 2004; 50(12):3762-71.