Fc gammaRIIIb triggers raft-dependent calcium influx in IgG-mediated responses in human neutrophils.
Human neutrophils constitutively express a unique combination of FcγRs, namely FcγRIIa and FcγRIIIb. Numerous lines of evidence support the concept that these FcγRs generate only partially characterized intracellular signals. However, despite the fact that both receptors are likely to be engaged simultaneously in a physiological setting, no recent publications have investigated the distinct, although partially convergent, results of their joint activation in IgG-dependent responses. To examine the significance of the co-expression of FcγRIIa and FcγRIIIb on human neutrophils, we analyzed the neutrophil responses to stimuli that engage these FcγRs, namely the phagocytosis of human IgG-opsonized zymosan and the responses to heat-aggregated IgGs. Blocking antibodies to either FcγR significantly decreased the phagocytic index and the stimulated production of superoxide anions. Both receptors are required for optimal IgG-dependent responses by human neutrophils. On the other hand, only blocking antibodies to FcγRIIIb, but not to FcγRIIa, inhibited the mobilization of calcium in response to heat-aggregated IgGs. Furthermore, phagocytosis of IgG-opsonized zymosan by human neutrophils required an extracellular influx of calcium that was blocked only by antibodies against FcγRIIIb. We also observed that this calcium influx as well as the IgG-dependent phagocytosis were dependent on the integrity of the plasma membrane detergent-resistant microdomains to which both isoforms were recruited following stimulation by heat-aggregated IgGs. These data clarify the mechanisms that regulate the FcγRs constitutively expressed on human neutrophils, describe a specific contribution of FcγRIIIb at the level of the mobilization of calcium, and provide evidence for a crucial role of detergent-resistant microdomains in this process.
Centre de Recherche du Centre Hospitalier Universitaire de Québec, Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Québec City, Québec G1V 4G2, Canada.
Louis
L
Marois
Guillaume
G
Paré
Myriam
M
Vaillancourt
Emmanuelle
E
Rollet-Labelle
Paul H
PH
Naccache
D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000276:immunology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000502:physiology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000502:physiology*
C428200:FCGR3B protein, human; C080568:Fc gamma receptor IIA; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; D017452:Receptors, IgG; D002118:Calcium