Open AccessNeutrophils in a mouse model of autoantibody‐mediated arthritis: Critical producers of Fc receptor γ, the receptor for C5a, and lymphocyte function−associated antigen 1
Author(s) -
Monach Paul A.,
Nigrovic Peter A.,
Chen Mei,
Hock Hanno,
Lee David M.,
Benoist Christophe,
Mathis Diane
Publication year - 2010
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.27238
Subject(s) - immunology , arthritis , proinflammatory cytokine , medicine , inflammation , tumor necrosis factor alpha , c5a receptor , receptor , inflammatory arthritis , immune system , complement system
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 B 4 likely contributes to inflammation but is not essential. Molecular requirements for neutrophil influx into joints become more permissive after inflammation is initiated.