Neutrophils in a mouse model of autoantibody‐mediated arthritis: Critical producers of Fc receptor γ, the receptor for C5a, and lymphocyte function− associated …

PA Monach, PA Nigrovic, M Chen, H Hock… - Arthritis & …, 2010 - Wiley Online Library
PA Monach, PA Nigrovic, M Chen, H Hock, DM Lee, C Benoist, D Mathis
Arthritis & Rheumatism, 2010Wiley Online Library
Objective Neutrophils represent a prominent component of inflammatory joint effusions and
are required for synovial inflammation in mouse models, but the mechanisms are poorly
understood. In this study, we developed a system with which to test the importance of the
production of specific factors by neutrophils in a mouse model of arthritis. Methods
Neutrophil‐deficient Gfi‐1–/–mice were administered sublethal doses of radiation and were
then engrafted with donor bone marrow cells (BMCs), which resulted in the production of …
Objective
Neutrophils represent a prominent component of inflammatory joint effusions and are required for synovial inflammation in mouse models, but the mechanisms are poorly understood. In this study, we developed a system with which to test the importance of the production of specific factors by neutrophils in a mouse model of arthritis.
Methods
Neutrophil‐deficient Gfi‐1–/– mice were administered sublethal doses of radiation and were then engrafted with donor bone marrow cells (BMCs), which resulted in the production of mature neutrophils within 2 weeks. By reconstituting with BMCs from mice lacking selected proinflammatory factors, we generated mice that specifically lacked these factors on their neutrophils. Arthritis was initiated by transfer of K/BxN serum to identify the role of defined neutrophil factors on the incidence and severity of arthritis.
Results
Neutrophils lacking the signaling chain of stimulatory Fc receptors (FcRγ–/–) were unable to elicit arthritis, but neutrophils lacking FcγRIII still did so. Neutrophils lacking the chemotactic or adhesion receptor C5a receptor (C5aR) or CD11a/lymphocyte function−associated antigen 1 (LFA‐1) also failed to initiate arthritis but could enter joints in which inflammation had been initiated by wild‐type neutrophils. Neutrophils unable to produce interleukin‐1α (IL‐1α) and IL‐1β (IL‐1α/β–/–) or leukotrienes (5‐lipoxygenase [5‐LOX–/–]) produced arthritis of intermediate severity. The inability of neutrophils to make tumor necrosis factor or to express receptors for tumor necrosis factor or IL‐1 had no effect on arthritis.
Conclusion
A novel transfer system was developed to identify neutrophil production of FcRγ, C5aR, and CD11a/LFA‐1 as critical components of autoantibody‐mediated arthritis. Neutrophil production of IL‐1 and leukotriene B4 likely contributes to inflammation but is not essential. Molecular requirements for neutrophil influx into joints become more permissive after inflammation is initiated.
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