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Mast cells jump start K/BxN serum transfer arthritis via IL-1

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Mast cell-deficient W/Wv mice are resistant to K/BxN serum transfer arthritis, and this resistance may be overcome by engraftment with mast cells. However, the pathways by which mast cells participate in arthritis remain unknown. Using a candidate mediator approach, we explored IL-1 as a potentially key mediator by which mast cells promote arthritis. As expected, IL-1α/β-deficient mice were completely resistant to arthritis. Short-term administration of exogenous IL-1 restored an attenuated arthritis course in these animals, consistent with an ongoing requirement for IL-1. Surprisingly, deficient W/Wv mice treated with IL-1 at disease induction displayed a full normal course of arthritis, demonstrating that exogenous IL-1 can bypass the need for mast cells. TNF proved unable to exert a similar effect. We therefore engrafted IL-1-/- bone marrow-derived mast cells (BMMC) into W/Wv animals and found that these animals displayed resistance to arthritis equivalent to nonengrafted W/Wv mice, consistent with an obligate role for IL-1 of mast cell origin. Exploring further the mechanisms by which mast cells may become activated in this IgG1-driven model, we found that BMMC stimulated in vitro via FcγRIII elaborated IL-1, while BMMC lacking this receptor were unable to mediate arthritis upon engraftment into W/Wv recipients. While BMMC engrafted into W/Wv animals disproportionately populate the spleen, we excluded a contribution from this aphysiologic mast cell population via splenectomy and by documenting that systemic levels of IL-1 were not detectable during arthritis initiation in engrafted animals. We conclude that mast cells local to the joint and activated via FcγRIII promote K/BxN serum transfer arthritis by production of IL-1, an activity that appears delimited to the initiation of disease (the 'jump start').

Acknowledgements

This work was supported by grant K08 AR051321 (PAN), Cogan Family Foundation and NIH R01 AI 59746-01 (DML).

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Keywords

  • Public Health
  • Arthritis
  • Cell Population
  • Mast Cell
  • Systemic Level