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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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Glomerular PMN accumulation in mice deficient in ICAM-1  and complement C3 or C4 (A), and proteinuria in C3-deficient mice (B).  Anti-GBM nephritis was induced in the aforementioned mice and their  wild-type counterparts, and glomerular PMN accumulation was determined 2 h after the induction of nephritis. The number of PMNs per  glomerular cross-section was not significantly different between any group  of animals and their controls. Proteinuria was examined in C3-deficient  mice and their wild-type counterparts 8 h after induction of nephritis.  C3- mice had significantly less proteinuria than wild-types. n = 4 for  each set of wild-type and complement knockout mice. n = 6 for wild-type and ICAM-1– mice. #P <0.05.
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Figure 3: Glomerular PMN accumulation in mice deficient in ICAM-1 and complement C3 or C4 (A), and proteinuria in C3-deficient mice (B). Anti-GBM nephritis was induced in the aforementioned mice and their wild-type counterparts, and glomerular PMN accumulation was determined 2 h after the induction of nephritis. The number of PMNs per glomerular cross-section was not significantly different between any group of animals and their controls. Proteinuria was examined in C3-deficient mice and their wild-type counterparts 8 h after induction of nephritis. C3- mice had significantly less proteinuria than wild-types. n = 4 for each set of wild-type and complement knockout mice. n = 6 for wild-type and ICAM-1– mice. #P <0.05.

Mentions: Divalent cation-dependent Mac-1 adhesion to ICAM-1 and iC3b occurs through the A domain of Mac-1 (1). To determine whether the engagement of Mac-1 with complement or ICAM-1 contributes to the reduction in PMN accumulation in Mac-1– mice 2 h after anti-GBM antiserum injection, groups of mice genetically deficient in C3 (the central component in complement activation), C4 (the classical pathway of complement activation triggered by antigen-antibody complexes), or ICAM-1 were examined 2 h after injection of anti-GBM antiserum. We observed no significant differences in glomerular PMN counts between ICAM-1–deficient mice and their wild-type mates, or C3- and C4-deficient mice and wild-type mice (Fig. 3). These data confirm that neutrophil accumulation is complement-independent (14, 15) and suggest that known Mac-1 ligands that are most likely to support neutrophil adhesion to the vessel wall do not play a role in this process.


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)

Glomerular PMN accumulation in mice deficient in ICAM-1  and complement C3 or C4 (A), and proteinuria in C3-deficient mice (B).  Anti-GBM nephritis was induced in the aforementioned mice and their  wild-type counterparts, and glomerular PMN accumulation was determined 2 h after the induction of nephritis. The number of PMNs per  glomerular cross-section was not significantly different between any group  of animals and their controls. Proteinuria was examined in C3-deficient  mice and their wild-type counterparts 8 h after induction of nephritis.  C3- mice had significantly less proteinuria than wild-types. n = 4 for  each set of wild-type and complement knockout mice. n = 6 for wild-type and ICAM-1– mice. #P <0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211718&req=5

Figure 3: Glomerular PMN accumulation in mice deficient in ICAM-1 and complement C3 or C4 (A), and proteinuria in C3-deficient mice (B). Anti-GBM nephritis was induced in the aforementioned mice and their wild-type counterparts, and glomerular PMN accumulation was determined 2 h after the induction of nephritis. The number of PMNs per glomerular cross-section was not significantly different between any group of animals and their controls. Proteinuria was examined in C3-deficient mice and their wild-type counterparts 8 h after induction of nephritis. C3- mice had significantly less proteinuria than wild-types. n = 4 for each set of wild-type and complement knockout mice. n = 6 for wild-type and ICAM-1– mice. #P <0.05.
Mentions: Divalent cation-dependent Mac-1 adhesion to ICAM-1 and iC3b occurs through the A domain of Mac-1 (1). To determine whether the engagement of Mac-1 with complement or ICAM-1 contributes to the reduction in PMN accumulation in Mac-1– mice 2 h after anti-GBM antiserum injection, groups of mice genetically deficient in C3 (the central component in complement activation), C4 (the classical pathway of complement activation triggered by antigen-antibody complexes), or ICAM-1 were examined 2 h after injection of anti-GBM antiserum. We observed no significant differences in glomerular PMN counts between ICAM-1–deficient mice and their wild-type mates, or C3- and C4-deficient mice and wild-type mice (Fig. 3). These data confirm that neutrophil accumulation is complement-independent (14, 15) and suggest that known Mac-1 ligands that are most likely to support neutrophil adhesion to the vessel wall do not play a role in this process.

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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Related in: MedlinePlus