Receptor tyrosine kinases Tyro3, Axl, and Mertk differentially contribute to antibody-induced arthritis

Tyro3, Axl, and Mertk (abbreviated TAMs) comprise a family of homologous type 1 receptor tyrosine kinases (RTKs) that have been implicated as inhibitory receptors that dampen inflammation, but their roles in the pathogenesis of rheumatoid arthritis remains understudied. Here, to investigate TAMs in an inflammatory arthritis model, antibodyinduced arthritis in single TAM-deficient mice ( Tyro3- KO, Axl-KO, Mertk-KO) was induced by K/BxN serum injection. Subsequently, joint inflammation and cytokine levels, as well as the expression of Fc gamma Rs and complement receptors were assessed in WT and TAM- deficient mice. Compared with littermate control mice, Axl(-/-) andMertk(-/-) mice developed more severe antibody-induced arthritis, while in contrast, Tyro3(-/-) mice showed diminished joint inflammation. Concomitantly, the levels of cytokines in joints ofAxl(-/-) andMertk(-/-) mice were also significantly increased, while cytokines in theTyro3(-/-) joint tissues were decreased. At the molecular and cellular level, TAMs showed distinct expression patterns, whereby monocytes expressed Axl and Mertk, but no Tyro3, while neutrophils expressed Axl and Tyro3 but little Mertk. Moreover, expression of Fc. receptors and C5aR showed different patterns with TAMs expression, whereby Fc gamma RIV was higher in monocytes ofAxl(-/-) andMertk(-/-) mice compared to wild-type mice, whileTyro3(-/-) neutrophils showed lower expression levels of Fc gamma RI, Fc gamma RIII and Fc gamma RIV. Finally, expression of C5aR was increased inMertk(-/-) monocytes, and was decreased inTyro3(-/-) neutrophils. These data indicate that Axl, Mertk and Tyro3 have distinct functions in antibody-induced arthritis, due in part to the differential regulation of cytokines production, as well as expression of Fc gamma Rs and C5aR.

Automated summary

This study investigates the role of Tyro3, Axl, and Mertk in the pathogenesis of rheumatoid arthritis. The results demonstrate that Axl and Mertk-deficient mice develop more severe antibody-induced arthritis, accompanied by increased levels of cytokines in the joints. In contrast, Tyro3-deficient mice show diminished joint inflammation. Furthermore, TAMs show distinct expression patterns, with monocytes expressing Axl and Mertk while neutrophils express Axl and Tyro3.