Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis
Sanae Ben Mkaddem, … , Pierre Bruhns, Renato C. Monteiro
Sanae Ben Mkaddem, … , Pierre Bruhns, Renato C. Monteiro
Published September 2, 2014; First published July 25, 2014
Citation Information: J Clin Invest. 2014;124(9):3945-3959. https://doi.org/10.1172/JCI74572.
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Categories: Research Article Inflammation

Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis

Abstract

Rheumatoid arthritis–associated (RA-associated) inflammation is mediated through the interaction between RA IgG immune complexes and IgG Fc receptors on immune cells. Polymorphisms within the gene encoding the human IgG Fc receptor IIA (hFcγRIIA) are associated with an increased risk of developing RA. Within the hFcγRIIA intracytoplasmic domain, there are 2 conserved tyrosine residues arranged in a noncanonical immunoreceptor tyrosine–based activation motif (ITAM). Here, we reveal that inhibitory engagement of the hFcγRIIA ITAM either with anti-hFcγRII F(ab′)2 fragments or intravenous hIgG (IVIg) ameliorates RA-associated inflammation, and this effect was characteristic of previously described inhibitory ITAM (ITAMi) signaling for hFcαRI and hFcγRIIIA, but only involves a single tyrosine. In hFcγRIIA-expressing mice, arthritis induction was inhibited following hFcγRIIA engagement. Moreover, hFcγRIIA ITAMi-signaling reduced ROS and inflammatory cytokine production through inhibition of guanine nucleotide exchange factor VAV-1 and IL-1 receptor–associated kinase 1 (IRAK-1), respectively. ITAMi signaling was mediated by tyrosine 304 (Y304) within the hFcγRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcγRII F(ab′)2 treatment of inflammatory synovial cells from RA patients inhibited ROS production through induction of ITAMi signaling. These data suggest that shifting constitutive hFcγRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation.

Authors

Sanae Ben Mkaddem, Gilles Hayem, Friederike Jönsson, Elisabetta Rossato, Erwan Boedec, Tarek Boussetta, Jamel El Benna, Pierre Launay, Jean-Michel Goujon, Marc Benhamou, Pierre Bruhns, Renato C. Monteiro

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Figure 1

Blocking F(ab′)2 fragments anti-hFcγRII or IVIg reduces edema and erythema as well as histological aspects of synovial hyperplasia in transgenic hFcγRIIA mice subjected to the CAIA model.

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Blocking F(ab′)2 fragments anti-hFcγRII or IVIg reduces edema and erythe...
(A) Arthritis protocol is shown. Mice were treated every 2 days with AT-10 F(ab′)2 or with an irrelevant mAb 320 F(ab′)2 (100 μg/20 g mouse) or IVIg (20 mg/20 g mouse) after disease induction by i.v. injection of an anti-CII mAb plus LPS. (B) Representative images of hind paws from WT (top panels) and hFcγRIIATg (bottom panels) mice at day 10. (C) Arthritis was evaluated by measuring the increase in ankle thickness (mm). Bars show mean ± SEM. (D) Microscopy analysis of H&E-stained tissue sections from ankles obtained from representative mice. Scale bars: 200 μm. (E) The inflammation scores were graded blind as follows: 0 (normal), 1 (mild), 2 (moderate), or 3 (severe). (F) Representative images of hind paws from FcRγ–/– (top panels) and FcγRIIATg–FcRγ–/– mice (bottom panels) at day 10 after the initial injection of anti-CII mAb. (G) Arthritis was evaluated by measuring the increase in ankle thickness (mm). *P < 0.05; n = 5.