Regulation of human neutrophil Fc? receptor IIa by C5a receptor promotes inflammatory arthritis in mice.

ABSTRACT: Rheumatoid arthritis culminates in joint destruction that, in mouse models of disease, is supported by innate immune molecules, including Fc? receptors (Fc?R) and complement. However, these findings may not be predictive of the outcome in humans, given the structural differences between murine and human activating Fc?R on neutrophils, a prominent component of joint exudates. The aim of this study was to examine the role of human neutrophil Fc?RIIa in the development of arthritis and probe the underlying mechanism by which Fc?RIIa initiates disease.K/BxN mouse serum transfer-induced arthritis was examined in mice expressing human Fc?RIIa on neutrophils but lacking their own activating Fc?R (?-chain-deficient mice). The role of mast cells, complement (C3 and C5a), and CD18 integrins in Fc?RIIa-initiated disease was examined using cell reconstitution approaches, inhibitors, and functional blocking antibodies, respectively. Crosstalk between the complement receptor C5aR and Fc?RIIa on neutrophils was evaluated in vitro.The expression of human Fc?RIIa on neutrophils was sufficient to restore susceptibility to K/BxN serum-induced neutrophil recruitment, synovitis, and bone destruction in ?-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 Fc?RIIa-mediated phagocytosis and oxidative burst in vitro.Human and murine activating Fc?R on neutrophils are not functionally equivalent, and in humans, they may play a primary role in arthritis. Crosstalk between neutrophil C5aR and Fc?RIIa is essential for disease progression, thus highlighting a new aspect of complement during the effector phase of inflammatory arthritis.

SUBMITTER: Tsuboi N 

PROVIDER: S-EPMC3128197 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature