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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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Time course of  glomerular PMN accumulation  and proteinuria. The number of  PMNs per glomerular cross section in Mac-1– (diamonds)  and wild-type (circles) mice were  assessed on esterase stained sections (A). Urine albumin excretion  (μg) was determined and expressed per mg of urinary creatinine to standardize for glomerular filtration rate (B). Glomerular  PMN accumulation in wild-type  and  mice was comparable at  1 h, and had increased in wild-type mice by 2 h but decreased  significantly at 2 and 4 h in the  Mac-1– mice. Strikingly,  proteinuria was absent in Mac-1– mice at all time points. n  = 7–10 mice/genotype at time  points 0–8 h and n = 4 mice/ genotype at the 18 h time point.  *P <0.005, #P <0.05 compared  to wild-type mice.
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Figure 1: Time course of glomerular PMN accumulation and proteinuria. The number of PMNs per glomerular cross section in Mac-1– (diamonds) and wild-type (circles) mice were assessed on esterase stained sections (A). Urine albumin excretion (μg) was determined and expressed per mg of urinary creatinine to standardize for glomerular filtration rate (B). Glomerular PMN accumulation in wild-type and mice was comparable at 1 h, and had increased in wild-type mice by 2 h but decreased significantly at 2 and 4 h in the Mac-1– mice. Strikingly, proteinuria was absent in Mac-1– mice at all time points. n = 7–10 mice/genotype at time points 0–8 h and n = 4 mice/ genotype at the 18 h time point. *P <0.005, #P <0.05 compared to wild-type mice.

Mentions: We injected anti-GBM antibody into Mac-1–deficient mice and their wild-type counterparts and measured glomerular neutrophil accumulation and proteinuria. 1 h after anti-serum injection, neutrophil glomerular accumulation was the same in and wild-type mice, suggesting that initial PMN recruitment is unaffected by Mac-1 deficiency. In contrast, at 2 h, the peak of PMN accumulation in wild-type animals, there was a significant reduction in the number of glomerular PMNs present in mice compared with wild-type. The difference in glomerular PMN counts between wild-type and mutant mice persisted at 4 h but by 18 h the counts declined to baseline levels in mice of both genotypes (Fig. 1 A). The peripheral blood PMN counts were similar in wild-type and mice at each experimental time point (data not shown).


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)

Time course of  glomerular PMN accumulation  and proteinuria. The number of  PMNs per glomerular cross section in Mac-1– (diamonds)  and wild-type (circles) mice were  assessed on esterase stained sections (A). Urine albumin excretion  (μg) was determined and expressed per mg of urinary creatinine to standardize for glomerular filtration rate (B). Glomerular  PMN accumulation in wild-type  and  mice was comparable at  1 h, and had increased in wild-type mice by 2 h but decreased  significantly at 2 and 4 h in the  Mac-1– mice. Strikingly,  proteinuria was absent in Mac-1– mice at all time points. n  = 7–10 mice/genotype at time  points 0–8 h and n = 4 mice/ genotype at the 18 h time point.  *P <0.005, #P <0.05 compared  to wild-type mice.
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Related In: Results  -  Collection

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

Figure 1: Time course of glomerular PMN accumulation and proteinuria. The number of PMNs per glomerular cross section in Mac-1– (diamonds) and wild-type (circles) mice were assessed on esterase stained sections (A). Urine albumin excretion (μg) was determined and expressed per mg of urinary creatinine to standardize for glomerular filtration rate (B). Glomerular PMN accumulation in wild-type and mice was comparable at 1 h, and had increased in wild-type mice by 2 h but decreased significantly at 2 and 4 h in the Mac-1– mice. Strikingly, proteinuria was absent in Mac-1– mice at all time points. n = 7–10 mice/genotype at time points 0–8 h and n = 4 mice/ genotype at the 18 h time point. *P <0.005, #P <0.05 compared to wild-type mice.
Mentions: We injected anti-GBM antibody into Mac-1–deficient mice and their wild-type counterparts and measured glomerular neutrophil accumulation and proteinuria. 1 h after anti-serum injection, neutrophil glomerular accumulation was the same in and wild-type mice, suggesting that initial PMN recruitment is unaffected by Mac-1 deficiency. In contrast, at 2 h, the peak of PMN accumulation in wild-type animals, there was a significant reduction in the number of glomerular PMNs present in mice compared with wild-type. The difference in glomerular PMN counts between wild-type and mutant mice persisted at 4 h but by 18 h the counts declined to baseline levels in mice of both genotypes (Fig. 1 A). The peripheral blood PMN counts were similar in wild-type and mice at each experimental time point (data not shown).

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