J. Exp. Med., Volume 186, Number 11, December 1, 1997 1853-1863

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

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

From the ^* Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115;  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 (_m2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fc receptors to facilitate immune complex (IC)-stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1-FcR 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-FcR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1-FcR 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.

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