Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Monocytes Are Required for Progression but Not for Initiation of Arthritis in Mouse Model of Autoantibody-Mediated Arthritis.
Misharin1, Alexander, Weber1, Evan, Perlman2, Harris R.
Monocytes and macrophages play essential role in pathogenesis of rheumatoid arthritis. However their role in initiation vs. perpetuation of inflammatory arthritis in rodent models is unclear. K/BxN serum-transfer model is a commonly used model for studying the effector phase of arthritis in mice. Role of the neuthrophils and mast cells in this model has been studied in details and it is now clear that these cells are essential for initiation of arthritis. Thought there are no doubts that monocytes and macrophages play very important role arthritis, it is less well studied. Previous studies have shown that mice depleted of macrophages by clodronate liposome treatment are completely resistant to K/BxN serum-induced arthritis and that reconstitution of these mice with macrophages from naïve animals reverses this resistance. However effect of clodronate is long-term and irreversible and it does not allow assessing role of monocytes and macrophages in different steps of effector phase of arthritis. Therefore we decided to take advantage of a conditional ablation system mediated by diphtheria toxin (DT) receptor (human hbEGF) expressed under CD11b promoter to study the effects of monocytes and macrophages depletion on the course of serum transfer arthritis.
Bone marrow from transgenic mice (C57Bl/6) expressing DTR under CD11b promoter was transferred into irradiated hosts. Six weeks after reconstitution all mice received injection of K/BxN serum and the severity of arthritis was assessed by measuring ankle width and clinical score for each limb on day 0, 2, 4, 7, 9, 11 and 14. Additionally mice were divided into three groups: arthritis only or control group did not receive DT treatment; initial monocytes depletionreceived DT on days -1 and 0; and continuous monocytes depletionreceived DT on days -1, 0 and every 48 hours till the end of experiment (days 2, 4, 6, 8, 10 and 12). To assess the effects of DT peripheral blood was obtained on day -6, day 0 and day 14 and analyzed by flow cytometry.
Single injection of DT did not affect T and B cells populations, but induced profound decrease of monocytes in peripheral blood (from 10.7% to 1.4% and from 13.2% to 1% for initially and continuously depleted mice, respectively). At the end of study levels of monocytes in mice that received only two injections of DT returned to baseline values and did not differ from control group (11.0% and 15.7%, correspondingly), while in mice that received continuous treatment with DT levels were significantly lower (3.87%). There was no decrease in neutrophils in DT-treated mice. All mice developed arthritis initially, however only mice continuously treated with DT failed to display progression of arthritits.
Continuous depletion of monocytes and macrophages prevents further progression of arthritis but not of initiation of K/BxN serum transfer arthritis. Taken together with recent findings about role of neutrophils in the effector phase of inflammatory arthritis, our work suggest that monocytes are necessary for its progression and bone damage while neutrophils are required for initiation of arthritis.
To cite this abstract, please use the following information:
Misharin, Alexander, Weber, Evan, Perlman, Harris R.; Monocytes Are Required for Progression but Not for Initiation of Arthritis in Mouse Model of Autoantibody-Mediated Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1723