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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 9 Pg. 3945-59 (Sep 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 25061875 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fc gamma receptor IIA
• Fcgr2b protein, mouse
• Immunoglobulins, Intravenous
• Intracellular Signaling Peptides and Proteins
• Reactive Oxygen Species
• Receptors, IgG
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• Syk protein, mouse
• Protein Tyrosine Phosphatase, Non-Receptor Type 6
• Ptpn6 protein, mouse

Topics

• Animals
• Arthritis, Rheumatoid (drug therapy, etiology, immunology)
• Female
• Immunoglobulins, Intravenous (therapeutic use)
• Intracellular Signaling Peptides and Proteins (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (physiology)
• Protein-Tyrosine Kinases (physiology)
• Reactive Oxygen Species (metabolism)
• Receptors, IgG (physiology)
• Signal Transduction
• Syk Kinase