title: Regulation of human neutrophil Fcγ receptor IIa by C5a receptor promotes inflammatory arthritis in mice.
abstract: OBJECTIVE
  Rheumatoid arthritis culminates in joint destruction that, in mouse models of disease, is supported by innate immune molecules, including Fcγ receptors (FcγR) and complement. However, these findings may not be predictive of the outcome in humans, given the structural differences between murine and human activating FcγR on neutrophils, a prominent component of joint exudates. The aim of this study was to examine the role of human neutrophil FcγRIIa in the development of arthritis and probe the underlying mechanism by which FcγRIIa initiates disease.
  
  
  METHODS
  K/BxN mouse serum transfer-induced arthritis was examined in mice expressing human FcγRIIa on neutrophils but lacking their own activating FcγR (γ-chain-deficient mice). The role of mast cells, complement (C3 and C5a), and CD18 integrins in FcγRIIa-initiated disease was examined using cell reconstitution approaches, inhibitors, and functional blocking antibodies, respectively. Crosstalk between the complement receptor C5aR and FcγRIIa on neutrophils was evaluated in vitro.
  
  
  RESULTS
  The expression of human FcγRIIa on neutrophils was sufficient to restore susceptibility to K/BxN serum-induced neutrophil recruitment, synovitis, and bone destruction in γ-chain-deficient mice. Joint inflammation was robust and proceeded even in the absence of mast cells and vascular permeability, features shown to contribute to disease in wild-type mice. Neutrophil recruitment was dependent on the presence of a CD18 integrin, lymphocyte function-associated antigen 1, and C5aR. In addition, C5aR significantly enhanced FcγRIIa-mediated phagocytosis and oxidative burst in vitro.
  
  
  CONCLUSIONS
  Human and murine activating FcγR on neutrophils are not functionally equivalent, and in humans, they may play a primary role in arthritis. Crosstalk between neutrophil C5aR and FcγRIIa is essential for disease progression, thus highlighting a new aspect of complement during the effector phase of inflammatory arthritis.
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernandez
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishi
authors.forename: Xavier
authors.initials: X
authors.lastname: Cullere
authors.forename: Divya
authors.initials: D
authors.lastname: Mekala
authors.forename: Melissa
authors.initials: M
authors.lastname: Hazen
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D020239:Receptor Cross-Talk / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D013045:Species Specificity; D013585:Synovitis / Q000276:immunology / Q000378:metabolism
chemical_list: C080568:Fc gamma receptor IIA; D044087:Receptor, Anaphylatoxin C5a; D017452:Receptors, IgG