FcγRIV is a mouse IgE receptor that resembles macrophage FcεRI in humans and promotes IgE-induced lung inflammation
David A. Mancardi, … , Marc Daëron, Pierre Bruhns
David A. Mancardi, … , Marc Daëron, Pierre Bruhns
Published October 23, 2008
Citation Information: J Clin Invest. 2008;118(11):3738-3750. https://doi.org/10.1172/JCI36452.
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Research Article Immunology

FcγRIV is a mouse IgE receptor that resembles macrophage FcεRI in humans and promotes IgE-induced lung inflammation

Abstract

FcγRIV is a recently identified mouse activating receptor for IgG2a and IgG2b that is expressed on monocytes, macrophages, and neutrophils; herein it is referred to as mFcγRIV. Although little is known about mFcγRIV, it has been proposed to be the mouse homolog of human FcγRIIIA (hFcγRIIIA) because of high sequence homology. Our work, however, has revealed what we believe to be new properties of mFcγRIV that endow this receptor with a previously unsuspected biological significance; we have shown that it is a low-affinity IgE receptor for all IgE allotypes. Although mFcγRIV functioned as a high-affinity IgG receptor, mFcγRIV-bound monomeric IgGs were readily displaced by IgE immune complexes. Engagement of mFcγRIV by IgE immune complexes induced bronchoalveolar and peritoneal macrophages to secrete cytokines, suggesting that mFcγRIV may be an equivalent of human FceRI(αγ), which is expressed by macrophages and neutrophils and especially in atopic individuals, rather than an equivalent of hFcγRIIIA, which has no affinity for IgE. Using mice lacking 3 FcγRs and 2 FceRs and expressing mFcγRIV only, we further demonstrated that mFcγRIV promotes IgE-induced lung inflammation. These data lead us to propose a mouse model of IgE-induced lung inflammation in which cooperation exists between mast cells and mFcγRIV-expressing lung cells. We therefore suggest that a similar cooperation may occur between mast cells and hFceRI-expressing lung cells in human allergic asthma.

Authors

David A. Mancardi, Bruno Iannascoli, Sylviane Hoos, Patrick England, Marc Daëron, Pierre Bruhns

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Figure 3

mFcγRIV is a high-affinity receptor for IgG2a/2b, but IgE ICs can bind to mFcγRIV in the presence of high IgG concentrations.

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mFcγRIV is a high-affinity receptor for IgG2a/2b, but IgE ICs can bind t...
(A) Histograms show the binding of monomeric mouse IgG1, IgG2a, or IgG2b (27–35) (10 μg/ml 100,000 g ultracentrifuged) to FcγR+ CHO, revealed by FITC-conjugated F(ab′)2 GaM. (B) Thioglycolate-elicited peritoneal macrophages from quintuple-KO mice were incubated with indicated concentrations of monomeric mouse Ig (μg/ml) and assayed for TNF-α secretion following incubation with F(ab′)2 GaM. Curves represent the percentage of cytotoxicity as a function of supernatant dilution. (C and D) Histograms show the binding of IgEa ICs (C38-2a) or IgEb ICs (C48-2b), (C) when diluted 1:2 in normal mouse serum or in PBS to mFcγRIV+ CHO or (D) when mFcγRIV+ CHO were preincubated with normal mouse serum diluted 1:2. Solid gray histograms show binding of Ag alone. IC binding was revealed by neutravidin staining. (E) mFcγRIV+ CHO were preincubated for 1 hour at 4°C with saturating concentrations of indicated IgG. Curves represent the percentage of IgG2a (open diamonds) or IgG2b (27–35) (filled diamonds) bound to these cells after an incubation at 37°C for increasing time periods. Insets show corresponding histograms at 0 (bold black line), 10 (dark gray line), 30 (black line), and 60 (light gray line) minutes. Solid gray histograms show binding of secondary Abs alone. a-, anti-. (F) SPR sensorgrams resulting from the injection of IgG2a or IgG2b (C48-4) onto immobilized mFcγRIV ectodomains. Data are representative of 2 (A–D and F) or 3 (E) experiments that gave similar results.