Expression and Modulation of the Human Immunoglobulin A Fc Receptor (CD89) and the FcR γ Chain on Myeloid Cells in Blood and Tissue

Neutrophil-mediated tumor cell lysis is more efficiently triggered by FcαRI (CD89), than by FcγRI (CD64). This difference is most evident in immature neutrophils in which FcγRI-mediated tumor cell lysis is absent. In this study, we show that FcR γ-chain-dependent functions (such as Ab-dependent cellular cytotoxicity and respiratory burst), as well as signaling (calcium mobilization and MAPK phosphorylation), were potently triggered via FcαRI, but not via FcγRI, in immature neutrophils. Internalization, an FcR γ-chain-independent function, was, however, effectively initiated via both receptors. These data suggest an impaired functional association between FcγRI and the FcR γ-chain, which prompted us to perform coimmunoprecipitation experiments. As a weaker association was observed between FcγRI and FcR γ-chain, compared with FcαRI and FcR γ-chain, our data support that differences between FcαRI- and FcγRI-mediated functions are attributable to dissimilarities in association with the FcR γ-chain.

Section: Discussionmentioning

confidence: 95%

FcR γ-Chain Dependent Signaling in Immature Neutrophils Is Mediated by FcαRI, but Not by FcγRI

Otten

Leusen

Rudolph

et al. 2007

“…Thus, one possible hypothesis is that the number of receptors cross-linked on the neutrophil cell surface may be insufficient to reach the threshold required for induction of survival and a synergistic OSCAR-TLR effect in the up-regulation of degranulation markers. In addition, neutrophils have been reported to express relatively low FcR␥ levels, compared with monocytes (26). A stoichiometric relationship between hOSCAR and the FcR␥ chain would be hypothesized, as is the case for the other receptors associated with FcR␥: one hOSCAR molecule would thus associate with a covalently linked dimer of the FcR␥ chain through ionic interaction.…”

Section: Discussionmentioning

confidence: 99%

Ligation of the FcRγ Chain-Associated Human Osteoclast-Associated Receptor Enhances the Proinflammatory Responses of Human Monocytes and Neutrophils

Merck¹,

Gaillard²,

Scuiller³

et al. 2006

We have previously described the human osteoclast associated receptor (hOSCAR), expressed in all cells of the myeloid lineage, and its immune functions. This receptor, which associates with the FcRγ chain to transduce an activating signal, induces calcium flux in monocytes and dendritic cells, and modulates specific responses of dendritic cells. In this study, we have examined the effects of hOSCAR ligation on various proinflammatory responses of monocytes and neutrophils. Monocytes stimulated via hOSCAR ligation released IL-8/CXCL8 and other chemokines such as epithelial neutrophil-activating peptide-78/CXCL5, macrophage-derived chemokine/CCL22, and MCP-1/CCL2 and up-regulated markers involved in cell adhesion and costimulatory functions. Monocytes stimulated via hOSCAR in the absence of survival factors had an increased life span. Although the life span of neutrophils was unaffected, these cells, when stimulated via hOSCAR, rapidly released reactive oxygen intermediates, degranulated lactoferrin, myeloperoxidase, and matrix metalloproteinase-9 and also secreted IL-8/CXCL8. Neutrophils also underwent changes in cell surface molecule expression with the cleavage of CD62L and increased expression of CD11b and CD66b after 2-h stimulations. Finally, we demonstrated synergy between hOSCAR and TLR ligands on both monocytes and neutrophils, with up to 8-fold increases in cytokine secretion when hOSCAR was cross-linked in the presence of LPS or R-848. Overall, our data demonstrate that hOSCAR is a functional receptor on monocytes and neutrophils, involved in the induction of the primary proinflammatory cascade and the initiation of downstream immune responses.

“…The observation that Fc␥RI expression decreases during neutrophil maturation suggests that Fc␥RI is not associated with FcR ␥-chain. Neutrophils were reported to express relatively low FcR ␥-chain levels, compared with monocytes (46). It is therefore possible that limited availability of FcR ␥-chain in immature neutrophils results in a favorable association with Fc␣RI due to a stronger electrostatic interaction, explaining the inability to induce tumor cell killing via Fc␥RI.…”

Section: Discussionmentioning

confidence: 99%

Immature Neutrophils Mediate Tumor Cell Killing via IgA but Not IgG Fc Receptors

Otten

Rudolph

Dechant

et al. 2005

129

130

Antitumor Abs are promising therapeutics for cancer. Currently, most Ab-based therapies focus on IgG Ab, which interact with IgG FcR (FcγR) on effector cells. In this study, we examined human and mouse neutrophil-mediated tumor cell lysis via targeting the IgA FcR, FcαRI (CD89), in more detail. FcαRI was the most effective FcR in triggering tumor cell killing, and initiated enhanced migration of neutrophils into tumor colonies. Importantly, immature neutrophils that are mobilized from the bone marrow upon G-CSF treatment efficiently triggered tumor cell lysis via FcαRI, but proved incapable of initiating tumor cell killing via FcγR. This may provide a rationale for the disappointing results observed in some earlier clinical trials in which patients were treated with G-CSF and antitumor Ab-targeting FcγR.