Reactive Oxygen Intermediates Enhance Fcγ Receptor Signaling and Amplify Phagocytic Capacity

Author:

Pricop Luminita1,Gokhale Jayashree1,Redecha Patricia1,Ng Sonia C.1,Salmon Jane E.1

Affiliation:

1. Department of Medicine, Hospital for Special Surgery and New York Presbyterian Hospital, Graduate Program in Immunology, Weill Medical College of Cornell University, New York, NY 10021

Abstract

AbstractReceptors for the Fc region of IgG (FcγR) mediate internalization of opsonized particles by human neutrophils (PMN) and mononuclear phagocytes. Cross-linking of FcγR leads to activation of protein tyrosine kinases and phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within FcγR subunits, both obligatory early signals for phagocytosis. Human PMN constitutively express two structurally distinct FcγR, FcγRIIa and FcγRIIIb, and can be induced to express FcγRI by IFN-γ. We have previously shown that stimulation of PMN through FcγRIIIb results in enhanced FcγRIIa-mediated phagocytic activity that is inhibited by catalase. In the present study, we have tested the hypothesis that reactive oxygen intermediates (ROI) have the capacity to regulate FcγR responses and defined a mechanism for this effect. We show that H2O2 augmented phagocytosis mediated by FcγRIIa and FcγRI in PMN and amplified receptor-triggered tyrosine phosphorylation of FcγR-associated ITAMs and signaling elements. Generation of endogenous oxidants in PMN by cross-linking FcγRIIIb similarly enhanced phosphorylation of FcγRIIa and Syk, a tyrosine kinase required for phagocytic function, in a catalase-sensitive manner. Our results provide a mechanism for priming phagocytes for enhanced responses to receptor-driven effects. ROI generated in an inflammatory milieu may stimulate quiescent cells to rapidly increase the magnitude of their effector function. Indeed, human monocytes incubated in the presence of stimulated PMN showed oxidant-induced increases in FcγRIIa-mediated phagocytosis. Definition of the role of oxidants as amplifiers of FcγR signaling identifies a target for therapeutic intervention in immune complex-mediated tissue injury.

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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