Microglial control of astrocytes in response to microbial metabolites.
Microglial control of astrocytes in response to microbial metabolites.
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DOI：
10.1038/s41586-018-0119-x
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发表时间：
2018-05
期刊：
影响因子：
64.8
通讯作者：
Quintana FJ
中科院分区：
文献类型：
--
作者：
Rothhammer V;Borucki DM;Tjon EC;Takenaka MC;Chao CC;Ardura-Fabregat A;de Lima KA;Gutiérrez-Vázquez C;Hewson P;Staszewski O;Blain M;Healy L;Neziraj T;Borio M;Wheeler M;Dragin LL;Laplaud DA;Antel J;Alvarez JI;Prinz M;Quintana FJ
小胶质细胞和星形胶质细胞调节中枢神经系统（CNS）中的炎症和神经变性。小胶质细胞调节星形胶质细胞中的促炎和神经毒性活性，但所涉及的机制尚未完全了解。在此我们报道了在多发性硬化症（MS）的实验性自身免疫性脑脊髓炎（EAE）模型中，小胶质细胞产生的TGF-α和VEGF-B调节星形胶质细胞的致病活动。小胶质细胞来源的TGF-α通过星形胶质细胞中的ErbB 1发挥作用，以限制其致病活性和EAE的发展。相反，小胶质细胞VEGF-B触发星形胶质细胞和EAE中的FLT-1信号传导。VEGF-B和TGF-α也参与人星形胶质细胞的小胶质细胞控制。此外，TGF-α和VEGF-B在CD 14+细胞中的表达与MS病变分期相关。最后，由植物植物群产生的饮食色氨酸（Trp）代谢产物控制小胶质细胞活化和TGF-α和VEGF-B的产生，通过芳香烃受体（AHR）介导的机制调节星形胶质细胞的转录程序和CNS炎症。总之，我们确定了新的积极和消极的监管机构，介导的小胶质细胞控制星形胶质细胞。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中致病活性的途径，抑制CNS炎症。这一途径可能会指导MS和其他神经系统疾病的新疗法。
Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS). Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood. Here we report that TGF-α and VEGF-B produced by microglia regulate astrocyte pathogenic activities in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Microglia-derived TGF-α acts via ErbB1 in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signaling in astrocytes and worsens EAE. VEGF-B and TGF-α also participate in the microglial control of human astrocytes. Furthermore, TGF-α and VEGF-B expression in CD14+ cells correlates with MS lesion stage. Finally, metabolites of dietary tryptophan (Trp) produced by the commensal flora control microglial activation and TGF-α and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor (AHR). In summary, we identified novel positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities in microglia and astrocytes, suppressing CNS inflammation. This pathway may guide new therapies for MS and other neurologic disorders.
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影响因子：
82.9
作者：
Rothhammer V;Mascanfroni ID;Bunse L;Takenaka MC;Kenison JE;Mayo L;Chao CC;Patel B;Yan R;Blain M;Alvarez JI;Kébir H;Anandasabapathy N;Izquierdo G;Jung S;Obholzer N;Pochet N;Clish CB;Prinz M;Prat A;Antel J;Quintana FJ
通讯作者：
Quintana FJ
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
32.4
作者：
Croxford, Andrew L.;Lanzinger, Margit;Becher, Burkhard
通讯作者：
Becher, Burkhard
影响因子：
4.4
作者：
Jack, CS;Arbour, N;Antel, JP
通讯作者：
Antel, JP
影响因子：
30.5
作者：
Buttgereit, Anne;Lelios, Iva;Greter, Melanie
通讯作者：
Greter, Melanie