title: A role for Mac-1 (CDIIb/CD18) in immune complex-stimulated neutrophil function in vivo: Mac-1 deficiency abrogates sustained Fcgamma receptor-dependent neutrophil adhesion and complement-dependent proteinuria in acute glomerulonephritis.
abstract: Mac-1 (alphambeta2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcgamma receptors to facilitate immune complex (IC)-stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1-FcgammaR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti-glomerular basement membrane (GBM) nephritis in wild-type and Mac-1-deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1- deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1-null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5-12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1-FcgammaR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1-FcgammaR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3-deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1-null mice.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tang
authors.forename: A
authors.initials: A
authors.lastname: Rosenkranz
authors.forename: K J
authors.initials: KJ
authors.lastname: Assmann
authors.forename: M J
authors.initials: MJ
authors.lastname: Goodman
authors.forename: J C
authors.initials: JC
authors.lastname: Gutierrez-Ramos
authors.forename: M C
authors.initials: MC
authors.lastname: Carroll
authors.forename: R S
authors.initials: RS
authors.lastname: Cotran
authors.forename: T N
authors.initials: TN
authors.lastname: Mayadas
mesh_terms: D000199:Actins / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000150:complications / Q000276:immunology* / Q000473:pathology; D001485:Basement Membrane / Q000276:immunology; D002199:Capillary Permeability; D002448:Cell Adhesion; D003179:Complement C3b / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology*; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D007105:Immune Complex Diseases / Q000150:complications / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology; D007518:Isoantibodies / Q000276:immunology / Q000633:toxicity; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D007975:Leukotriene B4 / Q000096:biosynthesis; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology* / Q000473:pathology; D017452:Receptors, IgG / Q000502:physiology*
chemical_list: D000199:Actins; D007518:Isoantibodies; D016177:Macrophage-1 Antigen; D017452:Receptors, IgG; D018799:Intercellular Adhesion Molecule-1; D007975:Leukotriene B4; D003179:Complement C3b; D003165:Complement System Proteins