title: Complement receptor 3 mediates renal protection in experimental C3 glomerulopathy.
abstract: C3 glomerulopathy is a complement-mediated renal disease that is frequently associated with abnormalities in regulation of the complement alternative pathway. Mice with deficiency of factor H (Cfh(-/-)), a negative alternative pathway regulator, are an established experimental model of C3 glomerulopathy in which complement C3 fragments including iC3b accumulate along the glomerular basement membrane. Here we show that deficiency of complement receptor 3 (CR3), the main receptor for iC3b, enhances the severity of spontaneous renal disease in Cfh(-/-) mice. This effect was found to be dependent on CR3 expression on bone marrow-derived cells. CR3 also mediated renal protection outside the setting of factor H deficiency, as shown by the development of enhanced renal injury in CR3-deficient mice during accelerated nephrotoxic nephritis. The iC3b-CR3 interaction downregulated the proinflammatory cytokine response of both murine and human macrophages to lipopolysaccharide stimulation in vitro, suggesting that the protective effect of CR3 on glomerular injury was mediated via modulation of macrophage-derived proinflammatory cytokines. Thus, CR3 has a protective role in glomerulonephritis and suggests that pharmacologic potentiation of the macrophage CR3 interaction with iC3b could be therapeutically beneficial.
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Barbour
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK.
authors.forename: Guang Sheng
authors.initials: GS
authors.lastname: Ling
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK.
authors.forename: Marieta M
authors.initials: MM
authors.lastname: Ruseva
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK; Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, London, UK.
authors.forename: Liliane
authors.initials: L
authors.lastname: Fossati-Jimack
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK. Electronic address: matthew.pickering@imperial.ac.uk.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics; D003176:Complement C3 / Q000378:metabolism*; D017242:Complement Factor H / Q000172:deficiency* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000378:metabolism*; D000081208:Hereditary Complement Deficiency Diseases; D007674:Kidney Diseases / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative
chemical_list: D039481:CD11b Antigen; D003176:Complement C3; D016207:Cytokines; D016177:Macrophage-1 Antigen; D017242:Complement Factor H
keywords: complement; glomerulonephritis; macrophages