Recombinant Gas6 augments Axl and facilitates immune restoration in an intracerebral hemorrhage mouse model
Recombinant Gas6 augments Axl and facilitates immune restoration in an intracerebral hemorrhage mouse model
复制标题
重组 Gas6 增强 Axl 并促进脑出血小鼠模型的免疫恢复。
DOI：
10.1177/0271678x16658490
复制
发表时间：
2017-06-01
影响因子：
6.3
通讯作者：
Zhang, John H.
中科院分区：
文献类型：
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作者：
Tong, Lu-sha;Shao, An-wen;Zhang, John H.
Axl是一种酪氨酸激酶受体，最近被鉴定为调节先天性免疫反应的重要组分。细胞因子信号转导抑制因子1和细胞因子信号转导抑制因子3是Axl诱导的有效负性炎症调节因子。本研究探讨了Axl信号通路在自体血注射脑出血小鼠模型免疫恢复中的作用。重组生长抑制特异性6（Gas6）和R428作为特异性激动剂和拮抗剂施用。应用通过siRNA体内敲低Axl或细胞因子信号传导抑制因子1和细胞因子信号传导抑制因子3。脑出血后，内源性Axl、可溶性Axl和Gas 6的表达增加，而细胞因子信号抑制因子1和细胞因子信号抑制因子3的表达受到抑制。重组生长停滞特异性6施用减轻脑水肿并改善神经行为表现。此外，观察到Axl磷酸化增强，可溶性Axl（sAxl）裂解，以及细胞因子信号传导抑制因子1和细胞因子信号传导抑制因子3的上调。体内敲除Axl和R428施用均消除了重组生长停滞特异性6对脑水肿的作用，并且还降低了细胞因子信号传导抑制因子1和细胞因子信号传导抑制因子3的表达。在体内敲除细胞因子信号抑制因子1和细胞因子信号抑制因子3会加重细胞因子的释放，尽管重组生长抑制特异性6。结论：Axl在脑出血后免疫功能恢复中起重要作用。重组生长停滞特异性6减轻脑出血后的脑损伤，可能是通过增强Axl磷酸化和细胞因子信号转导抑制因子1和细胞因子信号转导抑制因子3的产生。
Axl, a tyrosine kinase receptor, was recently identified as an essential component regulating innate immune response. Suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 are potent Axl-inducible negative inflammatory regulators. This study investigated the role of Axl signaling pathway in immune restoration in an autologous blood-injection mouse model of intracerebral hemorrhage. Recombinant growth arrest-specific 6 (Gas6) and R428 were administrated as specific agonist and antagonist. In vivo knockdown of Axl or suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 by siRNA was applied. After intracerebral hemorrhage, the expression of endogenous Axl, soluble Axl, and Gas6 was increased, whereas the expression of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 was inhibited. Recombinant growth arrest-specific 6 administration alleviated brain edema and improved neurobehavioral performances. Moreover, enhanced Axl phosphorylation with cleavage of soluble Axl (sAxl), and an upregulation of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 were observed. In vivo knockdown of Axl and R428 administration both abolished the effect of recombinant growth arrest-specific 6 on brain edema and also decreased the expression suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3. In vivo knockdown of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3 aggravated cytokine releasing despite of recombinant growth arrest-specific 6. In conclusion, Axl plays essential role in immune restoration after intracerebral hemorrhage. And recombinant growth arrest-specific 6 attenuated brain injury after intracerebral hemorrhage, probably by enhancing Axl phosphorylation and production of suppressor of cytokine signaling 1 and suppressor of cytokine signaling 3.