Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis
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
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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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 6

Both hFcγRIIA R131 and H131 allotypes mediate ITAMi signaling.

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Both hFcγRIIA R131 and H131 allotypes mediate ITAMi signaling. (A) Surfa...
(A) Surface-expression levels of hFcγRIIA allotypes in RBL-2H3 transfectants are shown compared with nontransfected cells (gray-shaded vs. open red histograms). (B) For ITAMi analysis, RBL-2H3 transfectants were incubated at 37°C with AT-10 F(ab′)2 (10 μg/ml) for the indicated times; FcγRIIA was immunoprecipitated from cell lysates with AT-10 (FcγRII) followed by immunoblotting with anti-Syk, anti–SHP-1, or anti-hFcγRIIA. The amount of SHP-1 and Syk in lysates was analyzed in parallel by immunoblotting. (C) IgE-sensitized RBL-2H3 transfectants were incubated overnight at 37°C with AT-10 F(ab′)2, and degranulation was triggered with DNP-HSA for 45 minutes. Net β-hexosaminidase release was determined. *P < 0.05.