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Arthritis Rheum. 2010 Mar;62(3):753-64. doi: 10.1002/art.27238.

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.

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  • 1Joslin Diabetes Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.

Abstract

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.

CONCLUSION:

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.

PMID:
20191628
[PubMed - indexed for MEDLINE]
PMCID:
PMC3057458
Free PMC Article
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