[HTML][HTML] Human neutrophil FcγRIIA regulation by C5aR promotes inflammatory arthritis in mice

N Tsuboi, T Ernandez, X Li, H Nishi… - Arthritis and …, 2011 - ncbi.nlm.nih.gov
N Tsuboi, T Ernandez, X Li, H Nishi, X Cullere, D Mekala, M Hazen, J Köhl, DM Lee…
Arthritis and Rheumatism, 2011ncbi.nlm.nih.gov
Objective Rheumatoid arthritis culminates in joint destruction that in mouse models of
disease, is supported by innate immune molecules including FcγRs and complement.
However, the results may not predict outcomes in humans given the structural differences
between murine and human activating FcγRs on neutrophils, a prominent component of joint
exudates. In this study, we examined the role of the human neutrophil FcγRIIA in the
development of arthritis and probed the underlying mechanism by which FcγRIIA initiated …
Abstract
Objective
Rheumatoid arthritis culminates in joint destruction that in mouse models of disease, is supported by innate immune molecules including FcγRs and complement. However, the results may not predict outcomes in humans given the structural differences between murine and human activating FcγRs on neutrophils, a prominent component of joint exudates. In this study, we examined the role of the human neutrophil FcγRIIA in the development of arthritis and probed the underlying mechanism by which FcγRIIA initiated disease.
Methods
K/BxN serum transfer-induced arthritis was examined in mice that express FcγRIIA on neutrophils but lack their own activating FcγRs (γ-chain-deficient). 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. Cross-talk between C5aR and FcγRIIA on neutrophils was evaluated in vitro.
Results
Neutrophil FcγRIIA expression 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, shown to contribute to disease in wild-type mice. Neutrophil recruitment was dependent on CD18 integrin LFA-1 and C5aR. C5aR in addition significantly enhanced FcγRIIA mediated phagocytosis and oxidative burst in vitro.
Conclusion
Human and murine activating FcγRs on neutrophils are not functionally equivalent, and in humans may play a primary role in arthritis. Cross-talk between neutrophil C5aR and FcγRIIA is essential for disease thus highlighting a new aspect of complement during the effector phase of inflammatory arthritis.
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