Neutrophils in a mouse model of autoantibody-mediated arthritis: critical producers of Fc receptor gamma, the receptor for C5a, and lymphocyte function-associated antigen 1.
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 (FcRgamma(-/-)) were unable to elicit arthritis, but neutrophils lacking FcgammaRIII 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-1alpha (IL-1alpha) and IL-1beta (IL-1alpha/beta(-/-)) 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.


CONCLUSIONS
A novel transfer system was developed to identify neutrophil production of FcRgamma, 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.
Monach
Paul A
PA
Joslin Diabetes Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Nigrovic
Peter A
PA
Chen
Mei
M
Hock
Hanno
H
Lee
David M
DM
Benoist
Christophe
C
Mathis
Diane
D
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases; D016026:Bone Marrow Transplantation; D005434:Flow Cytometry; D053582:Interleukin-1alpha / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis*; D051379:Mice; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D044087:Receptor, Anaphylatoxin C5a / Q000096:biosynthesis*; D017452:Receptors, IgG / Q000096:biosynthesis*
D001323:Autoantibodies; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015289:Leukotrienes; D016169:Lymphocyte Function-Associated Antigen-1; D044087:Receptor, Anaphylatoxin C5a; D017452:Receptors, IgG