Pepper, RJ; (2013) The role of Calprotectin (S100A8/A9) in the pathogenesis of glomerulonephritis and ANCA-associated vasculitis. Doctoral thesis , UCL (University College London).

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Abstract

Glomerulonephritis is a common cause of end-stage renal failure and a feature of ANCA-associated vasculitis (AAV). AAV is an example of a small vessel vasculitis, characterised by inflammation of the endothelium and glomeruli in which the interaction between leukocytes and endothelial cells play a crucial role. Macrophages have been demonstrated to have a critical role during the initiation and progression of glomerulonephritis. Calprotectin (also termed S100A8/A9, mrp8/14), is a complex of 2 small calcium binding proteins that is abundantly expressed in neutrophils and monocytes as well as early infiltrating macrophages and is a ligand of Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE). There is growing evidence in animal models and patients with autoimmune diseases, of calprotectin being involved in the inflammatory response, as well as being a marker of activation of innate immunity. I have initially characterised the presence of calprotectin-positive cells in renal biopsies of patients with focal and crescentic AAV glomerulonephritis, therefore linking the presence of these cells with renal outcome. Patients with active AAV have elevated serum calprotectin levels, as well as significant expression on neutrophils and monocytes, which although decrease during remission, does not normalise. I have demonstrated that mrp14-/- mice are protected from nephrotoxic nephritis, which is abrogated by use of LPS during disease progression. Bone-marrow derived macrophages (BMDMs) release pro-inflammatory cytokines following stimulation with calprotectin; mediated by TLR4. Mrp14-/- BMDMs do not respond to the pro-inflammatory stimulus of S100A8/A9. The co-culture of endothelial cells (EC) and wild-type BMDMs is pro-inflammatory unlike that of mrp14-/- BMDM and ECs. Mrp14-/- mesangial cells also have a decreased pro-inflammatory response. This work demonstrates that calprotectin has a role in experimental glomerulonephritis as well as AAV patients. This may improve our understanding of the inflammatory response and identify a new novel treatment targets.

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