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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: 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.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.

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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Model of putative role of Mac-1 in IC-stimulated glomerular PMN recruitment and proteinuria. (1) Anti-GBM antibody interacts with the  GBM forming immobilized ICs. (2) ICs are recognized by FcγR on PMNs. The adherent neutrophils have actin polymerization occurring at the periphery. This process does not require Mac-1. (3) PMNs adhere to immobilized ICs via the FcγR and require Mac-1 for reorganization of the actin cytoskeleton which promotes sustained spreading on the IC, allowing the PMNs to resist detachment into the flowing blood. Sustained spreading also promotes release of chemoattractants, which enhances neutrophil influx. (4) Mac-1 interaction with complement C3 leads to the release of azurophilic  granules containing cathepsin G and elastase, which are responsible for GBM damage. (5) PMNs detach and return to the bloodstream. In the absence of  Mac-1, PMNs adherent to ICs in step 2, detach, and return to the circulating blood as depicted in step 5 and Mac-1/C3–dependent proteinuria does not  occur. Endo.Fen, endothelial fenestrate; EC, endothelial cell.
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Figure 7: Model of putative role of Mac-1 in IC-stimulated glomerular PMN recruitment and proteinuria. (1) Anti-GBM antibody interacts with the GBM forming immobilized ICs. (2) ICs are recognized by FcγR on PMNs. The adherent neutrophils have actin polymerization occurring at the periphery. This process does not require Mac-1. (3) PMNs adhere to immobilized ICs via the FcγR and require Mac-1 for reorganization of the actin cytoskeleton which promotes sustained spreading on the IC, allowing the PMNs to resist detachment into the flowing blood. Sustained spreading also promotes release of chemoattractants, which enhances neutrophil influx. (4) Mac-1 interaction with complement C3 leads to the release of azurophilic granules containing cathepsin G and elastase, which are responsible for GBM damage. (5) PMNs detach and return to the bloodstream. In the absence of Mac-1, PMNs adherent to ICs in step 2, detach, and return to the circulating blood as depicted in step 5 and Mac-1/C3–dependent proteinuria does not occur. Endo.Fen, endothelial fenestrate; EC, endothelial cell.

Mentions: These results suggest the following model for the role of Mac-1 in IC-triggered neutrophil accumulation in this form of acute nephritis (Fig. 7). The initial attachment of neutrophils to ICs in the glomerular capillary wall occurs via Fc interactions with FcγR on the surface of neutrophils, and does not require Mac-1. Thus the early neutrophil accumulation is equal in both mutant and wild-type mice. However, Mac-1, through interactions with, or signals from, FcγR, is required for the F-actin reorganization necessary for sustained neutrophil spreading on ICs as shown in our in vitro studies. The functional interaction may be required for elaboration of mediators that signal further neutrophil influx, accounting for the increase in neutrophil accumulation in wild-type mice at 2 h, which does not occur in mutant mice. We have not identified the specific chemoattractants that are effected by Mac-1 deficiency. Production of LTB4, a powerful neutrophil chemoattractant, is not affected by Mac-1 deficiency or PMN spreading. Interaction of Mac-1 on PMNs with complement iC3b deposited on the vessel wall leads to the release of azurophilic granules, leading to protease-induced damage to the GBM and proteinuria, which is abrogated by Mac-1 or C3 deficiency. The glomerular PMN accumulation in this model is transient. There is evidence to suggest that the PMNs detach from the vessel wall, return to the bloodstream (16), and are probably cleared in the liver or spleen.


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)

Model of putative role of Mac-1 in IC-stimulated glomerular PMN recruitment and proteinuria. (1) Anti-GBM antibody interacts with the  GBM forming immobilized ICs. (2) ICs are recognized by FcγR on PMNs. The adherent neutrophils have actin polymerization occurring at the periphery. This process does not require Mac-1. (3) PMNs adhere to immobilized ICs via the FcγR and require Mac-1 for reorganization of the actin cytoskeleton which promotes sustained spreading on the IC, allowing the PMNs to resist detachment into the flowing blood. Sustained spreading also promotes release of chemoattractants, which enhances neutrophil influx. (4) Mac-1 interaction with complement C3 leads to the release of azurophilic  granules containing cathepsin G and elastase, which are responsible for GBM damage. (5) PMNs detach and return to the bloodstream. In the absence of  Mac-1, PMNs adherent to ICs in step 2, detach, and return to the circulating blood as depicted in step 5 and Mac-1/C3–dependent proteinuria does not  occur. Endo.Fen, endothelial fenestrate; EC, endothelial cell.
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Related In: Results  -  Collection

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Figure 7: Model of putative role of Mac-1 in IC-stimulated glomerular PMN recruitment and proteinuria. (1) Anti-GBM antibody interacts with the GBM forming immobilized ICs. (2) ICs are recognized by FcγR on PMNs. The adherent neutrophils have actin polymerization occurring at the periphery. This process does not require Mac-1. (3) PMNs adhere to immobilized ICs via the FcγR and require Mac-1 for reorganization of the actin cytoskeleton which promotes sustained spreading on the IC, allowing the PMNs to resist detachment into the flowing blood. Sustained spreading also promotes release of chemoattractants, which enhances neutrophil influx. (4) Mac-1 interaction with complement C3 leads to the release of azurophilic granules containing cathepsin G and elastase, which are responsible for GBM damage. (5) PMNs detach and return to the bloodstream. In the absence of Mac-1, PMNs adherent to ICs in step 2, detach, and return to the circulating blood as depicted in step 5 and Mac-1/C3–dependent proteinuria does not occur. Endo.Fen, endothelial fenestrate; EC, endothelial cell.
Mentions: These results suggest the following model for the role of Mac-1 in IC-triggered neutrophil accumulation in this form of acute nephritis (Fig. 7). The initial attachment of neutrophils to ICs in the glomerular capillary wall occurs via Fc interactions with FcγR on the surface of neutrophils, and does not require Mac-1. Thus the early neutrophil accumulation is equal in both mutant and wild-type mice. However, Mac-1, through interactions with, or signals from, FcγR, is required for the F-actin reorganization necessary for sustained neutrophil spreading on ICs as shown in our in vitro studies. The functional interaction may be required for elaboration of mediators that signal further neutrophil influx, accounting for the increase in neutrophil accumulation in wild-type mice at 2 h, which does not occur in mutant mice. We have not identified the specific chemoattractants that are effected by Mac-1 deficiency. Production of LTB4, a powerful neutrophil chemoattractant, is not affected by Mac-1 deficiency or PMN spreading. Interaction of Mac-1 on PMNs with complement iC3b deposited on the vessel wall leads to the release of azurophilic granules, leading to protease-induced damage to the GBM and proteinuria, which is abrogated by Mac-1 or C3 deficiency. The glomerular PMN accumulation in this model is transient. There is evidence to suggest that the PMNs detach from the vessel wall, return to the bloodstream (16), and are probably cleared in the liver or spleen.

Bottom Line: 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.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.

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