Background/Purpose:

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a hyper-inflammatory response in synovial joints. In joints of patients with active RA, few apoptotic cells are detected, and experimental data suggest that apoptotic cells delivered into the joint are protective. One of the receptors involved in uptake of apoptotic cells, a process called efferocytosis, is the Mer tyrosine kinase receptor. In addition, the Mer receptor is involved in an anti-inflammatory natural feedback mechanism. The local role of Mer during arthritis, however, has not been elucidated.

Methods: One day after the booster injection of collagen-induced arthritis (CIA) in mice, a commercially available antibody against Mer was injected intravenously or an adenovirus overexpressing the Mer ligand Protein S (Pros1) was injected intra-articularly into the knee joints. Mice were macroscopically scored until they were euthanized at day 30 or 31, respectively. Knee joints were taken for histology and synovial biopsies were isolated for cytokine profiling. The KRN serum transfer model was induced by two injections of serum on day 0 and 2 in either Mer-deficient mice or in wild type mice that overexpress Pros1 in their knee joints. Mice were macroscopically scored for 7 days or 14 days, respectively, and knee joints were taken for histology.

Results:

CIA mice treated with anti-Mer antibodies showed increased incidence and higher macroscopic knee score compared to those receiving an isotype control (IgG). Histological analysis showed significantly enhanced synovial inflammation, and higher synovial expression of the apoptosis marker caspase 3 after anti-Mer treatment. This indicates reduced efferocytosis in the anti-Mer treated animals. On the other hand, anti-Mer antibody treatment induced phosphorylation of the Mer receptor in these mice and upregulated synovial expression of the suppressor of cytokine signaling (SOCS) 1 and 3 genes. This could, however, not reduce the synovial expression of matrix-metalloproteinases (MMPs) 3, 9, and 13 and the pro-inflammatory mediator TNFα. In concordance with these data, CIA mice which locally overexpressed Pros1, a ligand that bridges apoptotic cells to the Mer receptor, in the knee joint showed a significant reduction in knee inflammation and expression of TNFα and several MMPs. Resolution of joint inflammation in the KRN-serum arthritis model is dependent on the development of apoptotic cells. We found that in Mer-deficient mice, induction of passive KRN arthritis caused an accelerated onset of disease and enhanced the macroscopic score in both knee and ankle joints. In contrast, intra-articular overexpression of Pros1 before KRN serum injections markedly reduced arthritis severity in wild type mice.

Conclusion: These data indicate the importance of Mer in controlling the severity and resolution of inflammation in experimental arthritis. Our data suggest that promoting Mer-mediated uptake of apoptotic cells in the arthritic joint might be therapeutically beneficial.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-mer-tyrosine-kinase-receptor-plays-a-protective-role-in-joint-inflammation-by-mediating-efferocytosis/