Convergence of Fcγ receptor IIA and Fcγ receptor IIIB signaling pathways in human neutrophils

Frank Chuang, Massimo Sassaroli, Jay C. Unkeless

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Human neutrophils (PMNs) express two receptors for the Fc domain of IgG: the transmembrane FcγRIIA, whose cytosolic sequence contains an immunoreceptor tyrosine-based activation motif, and the GPI-anchored FcγRIIIB. Cross-linking of FcγRIIIB induces cell activation, but the mechanism is still uncertain. We have used mAbs to cross-link selectively each of the two receptors and to assess their signaling phenotypes and functional relation. Cross-linking of FcγRIIIB induces intracellular Ca2+ release and receptor capping. The Ca2+ response is blocked by wortmannin and by N,N-dimethylsphingosine, inhibitors of phosphatidylinositol 3-kinase and sphingosine kinase, respectively. Identical dose-response curves are obtained for the Ca2+ release stimulated by Cross-linking FcγRIIA, implicating these two enzymes in a common signaling pathway. Wortmannin also inhibits capping of both receptors, but not receptor endocytosis. Fluorescence microscopy in double-labeled PMNs demonstrates that FcγRIIA colocalizes with cross-linked FcγRIIIB. The signaling phenotypes of the two receptors diverge only under frustrated phagocytosis conditions, where FcγRIIIB bound to substrate-immobilized Ab does not elicit cell spreading. We propose that FcγRIIIB signaling is conducted by molecules of FcγRIIA that are recruited to protein/lipid domains induced by clustered FcγRIIIB and, thus, are brought into juxtaposition for immunoreceptor tyrosine-based activation motif phosphorylation and activation of PMNs.

Original languageEnglish (US)
Pages (from-to)350-360
Number of pages11
JournalJournal of Immunology
Volume164
Issue number1
StatePublished - Jan 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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