| First Author | Ben Mkaddem S | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 9 | Pages | 3945-59 |
| PubMed ID | 25061875 | Mgi Jnum | J:215667 |
| Mgi Id | MGI:5606085 | Doi | 10.1172/JCI74572 |
| Citation | Ben Mkaddem S, et al. (2014) Shifting FcgammaRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis. J Clin Invest 124(9):3945-59 |
| abstractText | 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 (hFcgammaRIIA) are associated with an increased risk of developing RA. Within the hFcgammaRIIA 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 hFcgammaRIIA ITAM either with anti-hFcgammaRII 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 hFcalphaRI and hFcgammaRIIIA, but only involves a single tyrosine. In hFcgammaRIIA-expressing mice, arthritis induction was inhibited following hFcgammaRIIA engagement. Moreover, hFcgammaRIIA 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 hFcgammaRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcgammaRII 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 hFcgammaRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation. |
