Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Soochow University, Suzhou, 215123, China.
Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215123, China.
Cell Commun Signal. 2023 Aug 3;21(1):195. doi: 10.1186/s12964-023-01133-0.
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, antibody-induced 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 Fcγ Rs and complement receptors were assessed in WT and TAM-deficient mice. Compared with littermate control mice, Axl and Mertk mice developed more severe antibody-induced arthritis, while in contrast, Tyro3 mice showed diminished joint inflammation. Concomitantly, the levels of cytokines in joints of Axl and Mertk mice were also significantly increased, while cytokines in the Tyro3 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 Fcγ receptors and C5aR showed different patterns with TAMs expression, whereby FcγRIV was higher in monocytes of Axl and Mertk mice compared to wild-type mice, while Tyro3 neutrophils showed lower expression levels of FcγRI, FcγRIII and FcγRIV. Finally, expression of C5aR was increased in Mertk monocytes, and was decreased in Tyro3 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 FcγRs and C5aR. Video Abstract.
TYRO3、AXL 和 MERTK（简称 TAMs）属于同源的 I 型受体酪氨酸激酶（RTKs）家族，它们被认为是抑制炎症的受体，但它们在类风湿关节炎发病机制中的作用仍研究不足。在这里，为了在炎症性关节炎模型中研究 TAMs，通过 K/BxN 血清注射诱导单 TAM 缺陷小鼠（TYRO3-KO、AXL-KO、MERTK-KO）发生抗体诱导性关节炎。随后，在 WT 和 TAM 缺陷小鼠中评估关节炎症和细胞因子水平，以及 FcγR 和补体受体的表达。与同窝对照小鼠相比，AXL 和 MERTK 小鼠发展出更严重的抗体诱导性关节炎，而相反，TYRO3 小鼠表现出减轻的关节炎症。同时，AXL 和 MERTK 小鼠关节组织中的细胞因子水平也显著增加，而 TYRO3 关节组织中的细胞因子水平降低。在分子和细胞水平上，TAMs 表现出不同的表达模式，单核细胞表达 AXL 和 MERTK，但不表达 TYRO3，而中性粒细胞表达 AXL 和 TYRO3，但很少表达 MERTK。此外，FcγR 和 C5aR 的表达模式与 TAMs 的表达模式不同，AXL 和 MERTK 小鼠的单核细胞中 FcγRIV 的表达高于 WT 小鼠，而 TYRO3 中性粒细胞中 FcγRI、FcγRIII 和 FcγRIV 的表达水平较低。最后，Mertk 单核细胞中 C5aR 的表达增加，而 Tyro3 中性粒细胞中 C5aR 的表达减少。这些数据表明，AXL、Mertk 和 Tyro3 在抗体诱导性关节炎中具有不同的功能，部分原因是细胞因子产生的差异调节，以及 FcγR 和 C5aR 的表达。
