Session Title: Rheumatoid Arthritis - Animal Models I
Session Type: Abstract Submissions (ACR)
Background/Purpose: Monocytes and macrophages play a key role in the pathogenesis of rheumatoid arthritis. However, role of the individual subsets of monocytes and macrophages in the initiation, perpetuation and/or resolution of arthritis is unknown.
Methods: To uncover their role we utilized multiple strategies to deplete selective subsets of monocytes and macrophages in the K/BxN serum transfer arthritis mouse model: clodronate-loaded liposomes, diphtheria toxin and CD11b-DTR mice, aCCR2 antibody, adoptive transfer of monocytes.
Results: We found that contrary to the current dogma monocytes, and not neutrophils were necessary for initiation of arthritis. Moreover, we found that only non-classical Ly6C– monocytes were required for induction of arthritis, while classical Ly6C+ monocytes were dispensable. Further, we identified that naïve mouse joint contains heterogeneous population of macrophages, which differ in their origin, turnover and function, namely tissue-resident macrophages and bone marrow-derived macrophages. Selective depletion of the tissue-resident macrophages accelerated development of arthritis, while depletion of bone marrow-derived macrophages had no effect on arthritis. While blood monocytes were necessary for initiation and development of arthritis, they were not necessary for its resolution. In contrast, tissue macrophages were crucial for the resolution, since their depletion delayed resolution of arthritis and was associated with increased histological joint damage.
Conclusion: These data suggest that unlike other models (myocardial infarction, infectious diseases) resolution of arthritis does not require second wave of monocyte recruitment into the joint, but rather dependent on a molecular rheostat within macrophages, which controls the switch of their phenotype from “proinflammatory/classically activated” to a “wound healing/regulatory”. Phagocytosis of apoptotic neutrophils (efferocytosis) is potentially one of the mechanisms controlling this switch.
C. M. Cuda,
A. K. Gierut,
G. K. Haines III,
H. R. Perlman,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-role-for-ly6c-monocyte-subsets-and-joint-macrophages-in-mouse-model-of-rheumatoid-arthritis/