Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis

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 (hFc gamma RIIA) are associated with an increased risk of developing RA. Within the hFc gamma RIIA 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 hFc gamma RIIA ITAM either with anti-hFc gamma RII 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 hFc alpha RI and hFc gamma RIIIA, but only involves a single tyrosine. In hFc gamma RIIA-expressing mice, arthritis induction was inhibited following hFc gamma RIIA engagement. Moreover, hFc gamma RIIA 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 hFc gamma RIIA ITAM, which was required for recruitment of tyrosine kinase SW and tyrosine phosphatase SHP-1. Anti-hFc gamma RII 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 hFc gamma RIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation.