The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/12/1853/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 11, December 1, 1997 1853-1863

Articles

A Role for Mac-1 (CDIIb/CD18) in Immune Complex–stimulated Neutrophil Function In Vivo: Mac-1 Deficiency Abrogates Sustained Fc{gamma} Receptor–dependent Neutrophil Adhesion and Complement-dependent Proteinuria in Acute Glomerulonephritis

Tao Tang*, Alexander Rosenkranz*, Karel J.M. Assmann||, Michael J. Goodman*, Jose-Carlos Gutierrez-Ramos{ddagger}, Michael C. Carroll§, Ramzi S. Cotran*, and Tanya N. Mayadas*

From the * Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115; {ddagger} Center for Blood Research and § Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115; and || University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands

Mac-1 ({alpha}mβ2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fc{gamma} receptors to facilitate immune complex (IC)–stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1–Fc{gamma}R 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–Fc{gamma}R interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1–Fc{gamma}R 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.

Address correspondence to T.N. Mayadas, Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., Rm 404, Boston, MA 02115. Phone: 617-278-0194; FAX: 617-732-5933; E-mail: tmayadas{at}bustoff.bwh.harvard.edu

This research was supported by National Institutes of Health research grants NS-33296, DK-51643 (T.N. Mayadas), and PO1 HL-36028 (R.S. Cotran), and a grant from the National Multiple Sclerosis Society (T.N. Mayadas); a postdoctoral fellowship from the National Multiple Sclerosis Society (T. Tang); and an Erwin Schroedinger scholarship from the Austrian Science Foundation (A. Rosenkranz).

1 Abbreviations used in this paper: F-actin, filamentous actin; IC, immune complex; ICAM-1, intercellular adhesion molecule 1; GBM, glomerular basement membrane; LTB4, leukotriene B4; PMN, polymorphonuclear neutrophil.

Part of this work was previously presented as an abstract (1996. J. Vasc. Res. 33[S1]:A393).


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