Background/Purpose: Monocytes and macrophages play an essential function in the pathogenesis of rheumatoid arthritis. However, monocytes and macrophages are a heterogenous population and thus the role that the individual subsets play in the initiation, perpetuation and/or resolution phases of inflammatory arthritis is unknown.  Here we utilized strategies to deplete selective populations of monocyte and macrophage subsets but not neutrophils, to uncover the role of these cells in the development and resolution phases of arthritis.

Methods: C57BL/6 and CD11b-DTR transgenic mice were used in the study. Conditional monocyte/macrophage ablation was induced by repetitive administration of diphtheria toxin (DT) into CD11b-DTR transgenic mice during initiation and resolution phases of inflammatory arthritis.  Selective depletion of classic Ly6C+CCR2+ monocyte subset was achieved via administration of anti-CCR2 antibody during initiation and resolution phases of inflammatory arthritis.  Arthritis was induced using K/BxN serum transfer model and its severity was assessed using the clinical and histological scoring systems.

Results: Mice pretreated with DT and every three days for 14 days exhibited reduced numbers of peripheral blood monocytes but had no change in neutrophils. Subsequently, these mice initially developed K/BxN serum transfer induced arthritis but the arthritis was short lived and reached only a very moderate severity.  An additional study was also performed, which entailed the administration of DT at day 7 and every 3 days until days 14-17 following the initial injection of K/BxN serum. Surprisingly, deletion of monocytes and synovial macrophages markedly delayed the resolution phase of the K/BxN serum transfer induced arthritis.  In contrast, depletion of classic monocytes during both progressive phase and resolution of arthritis did not affect development or resolution of arthritis.

Conclusion: These data suggest a dual role for monocytes/macrophages in inflammatory arthritis that may be mediated by the local milieu.  Thus, macrophages in the joint may initially function as one of central inflammatory mediators of the destructive arthritis, while their phenotype may be polarized to a wound healing or regulatory type macrophage during the resolution of arthritis. The fact that classic monocytes were dispensable for both initiation and resolution of arthritis is of special interest, since most of the macrophages in the arthritis joint are monocyte derived. Taken together, these data indicate that targeting monocytes and macrophages as single type of monocyte/macrophage may not be therapeutically beneficial. Future therapies that identify the crucial type of macrophage at each stage of disease will lead to the development of novel therapeutics for RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/non-classical-monocytes-are-required-for-initiation-phase-while-macrophages-are-necessary-for-the-resolution-phase-in-the-kbxn-murine-of-inflammatory-arthritis/