title: S100A8/A9 (calprotectin) is critical for development of glomerulonephritis and promotes inflammatory leukocyte-renal cell interactions.
abstract: Glomerulonephritis is a common cause of end-stage renal disease. Infiltrating leukocytes interacting with renal cells play a critical role during the initiation and progression of glomerulonephritis, but the exact mechanisms are not clearly defined. By using the murine model of nephrotoxic nephritis, we investigated the role of S100A8/A9 [myeloid-related protein (MRP) 8/14, calprotectin] in promoting glomerulonephritis. In nephrotoxic nephritis, wild-type (WT) mice with glomerulonephritis have elevated serum levels of S100A8/A9, whereas mice deficient in MRP14 (S100a9(-/-)), and hence S100A8/A9, are significantly protected from disease. By using bone marrow transplants, we showed that MRP14 deficiency is required in both the hemopoietic and intrinsic cells for the protective effect. In vitro, both the WT bone marrow-derived macrophages and renal mesangial cells stimulated with S100A8/A9 secrete IL-6, CXCL1, and tumor necrosis factor α; however, Mrp14(-/-) cells exhibit significantly blunted proinflammatory responses. The interaction of WT bone marrow-derived macrophages with renal microvascular endothelial cells results in increased levels of monocyte chemotactic protein 1, IL-8, and IL-6 cytokines, which is attenuated in Mrp14(-/-) bone marrow-derived macrophages. Data shows that S100A8/A9 plays a critical role during glomerulonephritis, exerting and amplifying autocrine and paracrine proinflammatory effects on bone marrow-derived macrophages, renal endothelial cells, and mesangial cells. Therefore, complete S100A8/A9 blockade may be a new therapeutic target in glomerulonephritis.
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Pepper
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
authors.forename: Hsu-Han
authors.initials: HH
authors.lastname: Wang
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
authors.forename: Gayathri K
authors.initials: GK
authors.lastname: Rajakaruna
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Papakrivopoulou
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Department of Medicine, Centre for Complement and Inflammation, Imperial College London, London, United Kingdom.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.affiliation: Department of Medicine, Centre for Complement and Inflammation, Imperial College London, London, United Kingdom.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom. Electronic address: a.salama@ucl.ac.uk.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D039841:Leukocyte L1 Antigen Complex / Q000276:immunology* / Q000378:metabolism; D007962:Leukocytes; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D050527:Mesangial Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D039841:Leukocyte L1 Antigen Complex