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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.

Tang T, Rosenkranz A, Assmann KJ, Goodman MJ, Gutierrez-Ramos JC, Carroll MC, Cotran RS, Mayadas TN - J. Exp. Med. (1997)

Bottom Line: In vitro studies showed that spreading of Mac-1- 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.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- mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

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 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- 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- mice.

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Electron micrographs  of nephritic wild-type and Mac-1– mice kidneys 1 h after the  induction of anti-GBM nephritis. Representative pictures of intraglomerular capillary wild-type  (top) and Mac-1– (bottom) neutrophils are shown. Both sets of  glomeruli showed denudation of  the fenestrated endothelium and  had PMNs directly in contact with  the GBM. Arrowhead, fenestrated  endothelium; arrow, GBM; N,  Neutrophils. Original magnification: WT, ×15,500; Mac-1–,  ×13,500.
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Figure 2: Electron micrographs of nephritic wild-type and Mac-1– mice kidneys 1 h after the induction of anti-GBM nephritis. Representative pictures of intraglomerular capillary wild-type (top) and Mac-1– (bottom) neutrophils are shown. Both sets of glomeruli showed denudation of the fenestrated endothelium and had PMNs directly in contact with the GBM. Arrowhead, fenestrated endothelium; arrow, GBM; N, Neutrophils. Original magnification: WT, ×15,500; Mac-1–, ×13,500.

Mentions: Glomeruli of kidneys were examined by electron microscopy 1 h after anti-GBM injection. In mice of both genotypes, PMNs were observed either unattached in the capillary lumen or making contacts of varying extents with the GBM. The latter was associated with denudation of the fenestrated endothelium (Fig. 2), suggesting that Mac-1 deficiency does not protect against endothelial denudation by PMNs and that such damage is not responsible for the proteinuria in this model. However, the lack of proteinuria in Mac-1–deficient mice observed in Fig. 1 B suggests that mutant neutrophils are incapable of inducing functional GBM damage leading to proteinuria, which is characteristic of wild-type mice.


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.

Tang T, Rosenkranz A, Assmann KJ, Goodman MJ, Gutierrez-Ramos JC, Carroll MC, Cotran RS, Mayadas TN - J. Exp. Med. (1997)

Electron micrographs  of nephritic wild-type and Mac-1– mice kidneys 1 h after the  induction of anti-GBM nephritis. Representative pictures of intraglomerular capillary wild-type  (top) and Mac-1– (bottom) neutrophils are shown. Both sets of  glomeruli showed denudation of  the fenestrated endothelium and  had PMNs directly in contact with  the GBM. Arrowhead, fenestrated  endothelium; arrow, GBM; N,  Neutrophils. Original magnification: WT, ×15,500; Mac-1–,  ×13,500.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211718&req=5

Figure 2: Electron micrographs of nephritic wild-type and Mac-1– mice kidneys 1 h after the induction of anti-GBM nephritis. Representative pictures of intraglomerular capillary wild-type (top) and Mac-1– (bottom) neutrophils are shown. Both sets of glomeruli showed denudation of the fenestrated endothelium and had PMNs directly in contact with the GBM. Arrowhead, fenestrated endothelium; arrow, GBM; N, Neutrophils. Original magnification: WT, ×15,500; Mac-1–, ×13,500.
Mentions: Glomeruli of kidneys were examined by electron microscopy 1 h after anti-GBM injection. In mice of both genotypes, PMNs were observed either unattached in the capillary lumen or making contacts of varying extents with the GBM. The latter was associated with denudation of the fenestrated endothelium (Fig. 2), suggesting that Mac-1 deficiency does not protect against endothelial denudation by PMNs and that such damage is not responsible for the proteinuria in this model. However, the lack of proteinuria in Mac-1–deficient mice observed in Fig. 1 B suggests that mutant neutrophils are incapable of inducing functional GBM damage leading to proteinuria, which is characteristic of wild-type mice.

Bottom Line: In vitro studies showed that spreading of Mac-1- 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.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- mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

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 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- 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- mice.

Show MeSH
Related in: MedlinePlus