Microglial control of astrocytes in response to microbial metabolites,Nature

当前位置： X-MOL 学术 › Nature › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Microglial control of astrocytes in response to microbial metabolites
Nature ( IF 50.5 ) Pub Date : 2018-05-01 , DOI: 10.1038/s41586-018-0119-x
Veit Rothhammer ₁ , Davis M Borucki ₁ , Emily C Tjon ₁ , Maisa C Takenaka ₁ , Chun-Cheih Chao ₁ , Alberto Ardura-Fabregat ₂ , Kalil Alves de Lima ₁ , Cristina Gutiérrez-Vázquez ₁ , Patrick Hewson ₁ , Ori Staszewski ₂ , Manon Blain ₃ , Luke Healy ₃ , Tradite Neziraj ₁ , Matilde Borio ₁ , Michael Wheeler ₁ , Loic Lionel Dragin ₄ , David A Laplaud ₅ , Jack Antel ₃ , Jorge Ivan Alvarez ₄ , Marco Prinz _{2,

6} , Francisco J Quintana _{1,

7}

Affiliation

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1–3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.TGFα and VEGF-B produced by microglia regulate astrocyte function in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

中文翻译：

响应微生物代谢物的星形胶质细胞的小胶质细胞控制

小胶质细胞和星形胶质细胞调节中枢神经系统 (CNS)1-3 的炎症和神经变性。小胶质细胞调节星形胶质细胞的促炎和神经毒性活动，但所涉及的机制尚不完全清楚4,5。在这里，我们报告了小胶质细胞产生的 TGFα 和 VEGF-B 在多发性硬化的实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型中调节星形胶质细胞的致病活性。小胶质细胞衍生的 TGFα 通过星形胶质细胞中的 ErbB1 受体起作用，以限制其致病活性和 EAE 发展。相反，小胶质细胞 VEGF-B 会触发星形胶质细胞中的 FLT-1 信号并使 EAE 恶化。VEGF-B 和 TGFα 也参与人星形胶质细胞的小胶质细胞控制。此外，CD14+ 细胞中 TGFα 和 VEGF-B 的表达与多发性硬化病变阶段相关。最后，由共生菌群产生的膳食色氨酸代谢物控制小胶质细胞激活和 TGFα 和 VEGF-B 的产生，通过芳烃受体介导的机制调节星形胶质细胞的转录程序和中枢神经系统炎症。总之，我们确定了介导星形胶质细胞小胶质细胞控制的正负调节因子。此外，这些发现定义了微生物代谢物限制小胶质细胞和星形胶质细胞的致病活性并抑制中枢神经系统炎症的途径。该通路可以指导多发性硬化症和其他神经系统疾病的新疗法。小胶质细胞产生的 TGFα 和 VEGF-B 在多发性硬化症的实验性自身免疫性脑脊髓炎模型中调节星形胶质细胞的功能。

更新日期：2018-05-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11