Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure.
Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure.
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DOI：
10.1002/glia.23214
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发表时间：
2017-12
期刊：
影响因子：
6.2
通讯作者：
Shafit-Zagardo B
中科院分区：
文献类型：
--
作者：
Ray AK;DuBois JC;Gruber RC;Guzik HM;Gulinello ME;Perumal G;Raine C;Kozakiewicz L;Williamson J;Shafit-Zagardo B
受体酪氨酸激酶 (RTK) 的 TAM（Tyro3、Axl 和 MerTK）家族及其配体 Gas6 和 ProS1 对于先天免疫反应和中枢神经系统 (CNS) 稳态非常重要。虽然只有 Gas6 直接激活 Axl，但 ProS1 激活 Tyro3/MerTK 可以通过受体异二聚化间接激活 Axl。因此，我们生成了 Gas6−/−Axl−/− 双敲除 (DKO) 小鼠，以专门检查该信号传导轴的贡献，同时通过 Tyro3 和 MerTK 保留 ProS1 信号传导。我们发现幼年 DKO 小鼠和 WT 小鼠的髓鞘形成相当，胼胝体中的轴突和少突胶质细胞数量相同。使用脱髓鞘/髓鞘再生的铜宗模型，透射电子显微镜显示，在从 6 周铜宗饮食恢复 3 周后，DKO 小鼠的大脑中存在广泛的轴突肿胀，其中含有自噬溶酶体和多泡体，并且有较少的有髓轴突。免疫荧光染色分析表明，DKO 小鼠中 SMI32+ 和 APP+ 轴突较多，髓磷脂较少。各组小鼠之间 GFAP+ 星形胶质细胞或 Iba1+ 小胶质细胞/巨噬细胞的数量没有显着差异。然而，在铜宗治疗和恢复 6 周后，DKO 小鼠促炎细胞因子增加，细胞因子信号传导抑制因子 (SOCS) mRNA 表达发生改变，支持 Gas6-Axl 信号传导在促炎细胞因子抑制中的作用。相对于接受铜宗的 WT 小鼠，DKO 小鼠也观察到显着的运动缺陷。这些数据表明，Gas6-Axl 信号传导在维持轴突完整性以及调节和减少 CNS 炎症方面发挥着重要作用，而 ProS1/Tyro3/MerTK 信号传导无法补偿这些炎症。
The TAM (Tyro3, Axl, and MerTK) family of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and ProS1, are important for innate immune responses and central nervous system (CNS) homeostasis. While only Gas6 directly activates Axl, ProS1 activation of Tyro3/MerTK can indirectly activate Axl through receptor heterodimerization. Therefore, we generated Gas6−/−Axl−/− double knockout (DKO) mice to specifically examine the contribution of this signaling axis while retaining ProS1 signaling through Tyro3 and MerTK. We found that naïve young adult DKO and WT mice have comparable myelination and equal numbers of axons and oligodendrocytes in the corpus callosum. Using the cuprizone model of demyelination/remyelination, transmission electron microscopy revealed extensive axonal swellings containing autophagolysosomes and multivesicular bodies, and fewer myelinated axons in brains of DKO mice at 3-weeks recovery from a 6-week cuprizone diet. Analysis of immunofluorescent staining demonstrated more SMI32+ and APP+ axons and less myelin in the DKO mice. There were no significant differences in the number of GFAP+ astrocytes or Iba1+ microglia/macrophages between the groups of mice. However, at 6-weeks cuprizone and recovery, DKO mice had increased proinflammatory cytokine and altered suppressor of cytokine signaling (SOCS) mRNA expression supporting a role for Gas6-Axl signaling in proinflammatory cytokine suppression. Significant motor deficits in DKO mice relative to WT mice on cuprizone were also observed. These data suggest that Gas6-Axl signaling plays an important role in maintaining axonal integrity and regulating and reducing CNS inflammation that cannot be compensated for by ProS1/Tyro3/MerTK signaling.
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