Signal-Specific Activation and Regulation of Human Neutrophil Fcγ Receptors

Abstract

FcγRs with the ITIM domain have been shown to regulate the inflammatory signal delivered by the ITAM-containing FcγRs. In this study, we demonstrate that the function of human neutrophil FcγR type IIA (CD32A) is regulated in a distinct manner by different cell activation signals at the ligand-binding stage. Activation of neutrophils with fMLP up-regulated the ligand-binding function of CD32A, whereas PMA-mediated activation completely abolished ligand binding without altering CD32A expression. Furthermore, PMA treatment also abolished CD16B-dependent ligand binding irrespective of the level of expression. The effect of PMA was cell type specific, because the ligand-binding function of CD32A expressed on cultured cells such as K562 and CHO-CD32A transfectants was not affected by PMA. Interestingly, phorbol 12,13-dibutyrate, another phorbol ester, and IL-8 up-regulated CD32A-dependent ligand-binding function. These results demonstrate that regulation of CD32A-dependent ligand binding in human neutrophils is not only cell type specific but also activation signal specific. Moreover, these results suggest the possibility that signals delivered to neutrophils by various inflammatory stimuli can exert opposing effects on the function of human FcγRs, representing a novel inside-out regulatory mechanism of FcγR ligand binding.

Staphylococcus aureus Formyl Peptide Receptor–like 1 Inhibitor (FLIPr) and Its Homologue FLIPr-like Are Potent FcγR Antagonists That Inhibit IgG-Mediated Effector Functions

“…Cross-talk between FPR and FcgR is described. Activation of FPR1 by fMLF, the archetype formylated peptide originating from growing bacteria, results in an increased surface expression of many cellular receptors, including FcgR (39,40). Furthermore, it was suggested that signaling of FcgRIIIb might involve FPR and that activation of FcgRIIIb on human neutrophils modulates fMLF binding and migration (41).…”

Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between FcγRIIa and CXCR1/2

“…41 Furthermore, the affinities of Fc␥RIIa and Fc␥RIIIb for human IgG 1 , the isotype of the lupus AECA purified in the study, are similar, each having an affinity constant (K A ) of 10 Ϫ6 to 10 Ϫ7 M Ϫ1 . 16,32,42 IL-8 is known to augment the capacity of human PMN Fc␥RIIa to bind IgG-coated erythrocytes 43 and also to lead to the rapid clustering of LFA-1 into high-avidity patches on the PMN surface. 44 This raises the possibility that Fc␥RIIa might also cluster in response to IL-8 stimulation, thereby increasing avidity and the chance of receptor cross-linking by surface-bound IgG.…”

FcγRIIA and FcγRIIIB Mediate Nuclear Factor Activation through Separate Signaling Pathways in Human Neutrophils

“…1C). Fc␥RIIIB had also been suggested to be functionally coupled to the fMLP receptor (29,30), but treating cells with the G protein inhibitor pertussis toxin did not block Fc␥RIIIB-mediated Elk-1 activation (Fig. 1C).…”

“…Others have suggested that Fc␥RIIIB is functionally coupled to the neutrophil fMLP receptor (29,30), but the possibility that Fc␥RIIIB signals via this G protein-coupled receptor has not been explored. Treatment of neutrophils with the Tec family kinase inhibitor LFM-A13 did not have any effect on the Fc␥RIIIB-induced activation of Elk-1 in the nucleus (Fig.…”