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S100A8/A9 (Calprotectin) Is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte-Renal Cell Interactions.

Pepper, RJ; Wang, HH; Rajakaruna, GK; Papakrivopoulou, E; Vogl, T; Pusey, CD; Cook, HT; (2015) S100A8/A9 (Calprotectin) Is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte-Renal Cell Interactions. The American Journal of Pathology , 185 (5) 1264 - 1274. 10.1016/j.ajpath.2015.01.015. Green open access

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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.

Type: Article
Title: S100A8/A9 (Calprotectin) Is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte-Renal Cell Interactions.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajpath.2015.01.015
Publisher version: http://dx.doi.org/10.1016/j.ajpath.2015.01.015
Language: English
Additional information: © Elsevier 2015. This is an open access article made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1468133
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