Background/Purpose:  Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by an unrestrained inflammatory response in selective, anatomically distinct synovial joints. The innate immune system plays a crucial role in the pathogenesis of RA which is highlighted by the efficacy of biologicals directed against cytokines that are predominantly produced by macrophages. One family of tyrosine kinase receptors involved in an anti-inflammatory feedback mechanism are Tyro3, Axl and Mer (gene name Mertk; TAM). Of importance, Axl and Mer are mainly expressed on the antigen-presenting cells of the innate immune system. The plasma level of the TAM receptor ligand Growth arrest specific 6 (Gas6) is significantly reduced in RA patients suggesting this feedback mechanism is impaired in RA. We investigated the individual role of the TAM receptors Axl and Mer in an inflammatory model of arthritis that is driven by macrophages.

Methods:  The KRN serum transfer model of arthritis was induced by two intraperitoneal injections of arthritic K/BxN serum in Axl^-/-, Mertk^-/-, Axl^-/-Mertk^-/- and wild-type (WT) mice. Ankle joints were macroscopically scored for 7 days. At day 2 and 7, ankle joints were isolated for histology and immunohistochemistry. At day 7, knee joints were macroscopically scored and isolated for histology and immunohistochemistry.

Results:  Mertk^-/- mice had an increased macroscopic ankle score until day 4 whereas Axl^-/- mice had an enhanced macroscopic score from day 4 until the end of the experiment at day 7. Histology of the ankle joints showed significantly more inflammation in Mertk^-/- mice at day 2 and increased arthritis pathology in Axl^-/- mice at day 7, reflecting the macroscopic ankle scores. Histological analysis of ankle joints of Axl^-/-Mertk^-/- mice at day 7 showed enhanced inflammation and cartilage depletion compared to both Axl^-/- and WT mice, indicating an additive effect of Axl and Mer deficiency. In contrast to the ankle joints at day 7, enhanced macroscopic score and arthritis pathology in the knee joints of Mertk^-/- mice, compared to WT mice, was observed. No differences on arthritis pathology were detected in the knee joints of Axl^-/-Mertk^-/- compared to Mertk^-/- mice. To explain the discrepancy of Axl involvement between ankle and knee at day 7, we looked for Axl expression in synovium before the onset of arthritis. The cells in the lining layer of ankle synovium were strikingly Axl positive whereas the synovium of the knee joints was Axl negative.

Conclusion:  These findings identify the TAM receptors Axl and Mer as important players in arthritis. The Mer receptor plays a protective role at the onset of arthritis whereas the Axl receptor takes over this role in established disease in ankle joints. In the knee joints, however, Mer but not Axl, plays a prominent protective role, likely due to the lack of Axl in naïve knee joints. These findings highlight differences in topographically distinct synovial joints in inflammatory arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-tam-receptors-axl-and-mer-play-a-protective-role-in-a-temporal-and-spatial-manner-in-inflammatory-arthritis/