title: 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
authors: S
authors: Ben Mkaddem
authors: Gilles
authors: G
authors: Hayem
authors: Friederike
authors: F
authors: Jönsson
authors: Elisabetta
authors: E
authors: Rossato
authors: Erwan
authors: E
authors: Boedec
authors: Tarek
authors: T
authors: Boussetta
authors: Jamel
authors: J
authors: El Benna
authors: Pierre
authors: P
authors: Launay
authors: Jean-Michel
authors: JM
authors: Goujon
authors: Marc
authors: M
authors: Benhamou
authors: Pierre
authors: P
authors: Bruhns
authors: Renato C
authors: RC
authors: Monteiro
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000209:etiology / Q000276:immunology*; D005260:Female; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: C080568:Fc gamma receptor IIA; C499172:Fcgr2b protein, mouse; D016756:Immunoglobulins, Intravenous; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse