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Intravenous immunoglobulins modulate neutrophil activation and vascular injury through Fc?RIII and SHP-1.

ABSTRACT: Intravascular neutrophil recruitment and activation are key pathogenic factors that contribute to vascular injury. Intravenous immunoglobulin (IVIG) has been shown to have a beneficial effect in systemic inflammatory disorders; however, the mechanisms underlying IVIG's inhibitory effect on neutrophil recruitment and activation are not understood.We studied the mechanisms by which IVIG exerts protection from neutrophil-mediated acute vascular injury.We examined neutrophil behavior in response to IVIG in vivo, using real-time intravital microscopy. We found that an antibody that blocks both Fc?RIII and its inhibitory receptor counterpart, Fc?RIIB, abrogated the inhibitory effect of IVIG on leukocyte recruitment and heterotypic red blood cell (RBC) interactions with adherent leukocytes in wild-type mice. In the context of sickle cell disease, the blockade of both Fc?RIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of Fc?RIIB- and Fc?RIII-deficient mice revealed the predominant expression of Fc?RIII on circulating neutrophils. Fc?RIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas Fc?RIIB was dispensable. In addition, Fc?RIII-induced IVIG anti-inflammatory activity in neutrophils was mediated by recruitment of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Indeed, the protective effect of IVIG on leukocyte recruitment and activation was abrogated in SHP-1-mutant mice.Fc?RIII, a classic activating receptor, has an unexpected inhibitory role on neutrophil adhesion and activation via recruitment of SHP-1 in response to IVIG. Our results identify SHP-1 as a therapeutic target in neutrophil-mediated vascular injury.

SUBMITTER: Jang JE

PROVIDER: S-EPMC3351009 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1.

Jang Jung-Eun JE Hidalgo Andrés A Frenette Paul S PS

Circulation research 20120313 8

<h4>Rationale</h4>Intravascular neutrophil recruitment and activation are key pathogenic factors that contribute to vascular injury. Intravenous immunoglobulin (IVIG) has been shown to have a beneficial effect in systemic inflammatory disorders; however, the mechanisms underlying IVIG's inhibitory effect on neutrophil recruitment and activation are not understood.<h4>Objective</h4>We studied the mechanisms by which IVIG exerts protection from neutrophil-mediated acute vascular injury.<h4>Methods ...[more]

PMID: 22415018

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Project description:To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury.Randomized controlled laboratory experiment.University animal research facility.Eighteen chronically instrumented sheep.Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses.Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ? 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding.The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.

Project description:Atherogenesis and arterial remodeling following mechanical injury are driven by inflammation and mononuclear cell infiltration. The binding of immune complexes (ICs) to immunoglobulin (Ig)-Fc gamma receptors (Fc?Rs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of Fc?RIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of Fc?RIII in diet-induced "chronic" atherosclerosis. Fc?rIII-/-/Apoe-/- and control Apoe-/- mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD). Fc?rIII deficiency mitigated neointimal plaque formation and lesional macrophage accumulation, and enhanced neointimal vascular smooth muscle cell (VSMC) numbers. This went along with a reduced expression of tumor necrosis factor-? (TNF-?), monocyte chemoattractant protein-1 (MCP-1/CCL2), and vascular cell adhesion molecule-1 (VCAM-1) in the neointimal lesions. Interestingly, in a chronic model of diet-induced atherosclerosis, we unraveled a dichotomic role of Fc?RIII in an early versus advanced stage of the disease. While Fc?rIII deficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end, Fc?rIII deficiency attenuated pro-inflammatory responses in early atherosclerosis but promoted these events in advanced stages. Analysis of the mechanism(s) underlying the athero-promoting effect of Fc?rIII deficiency in late-stage atherosclerosis revealed increased serum levels of anti-oxidized-LDL immunoglobulins IgG2c and IgG2b. This was paralleled by enhanced lesional accumulation of IgGs without affecting levels of complement-activated products C5a or C5ar1, Fc?RII, and Fc?RIV. Moreover, Fc?rIII-deficient macrophages expressed more Fc?rII, Tnf-?, and Il-1? mRNA when exposed to IgG1 or oxLDL-IgG1 ICs in vitro, and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activating Fc?RIII limits neointima formation after arterial injury in atherosclerosis-prone mice as well as early stage chronic atherosclerosis, but augments late-stage atherosclerosis suggesting a dual role of Fc?RIII in atherogenic inflammation.

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Intravenous immunoglobulins modulate neutrophil activation and vascular injury through Fc?RIII and SHP-1.

Publications

Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1.

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