Activation of both transforming growth factor-β and bone morphogenetic protein signalling pathways upon traumatic brain injury restrains pro-inflammatory and boosts tissue reparatory responses of reactive astrocytes and microglia
Activation of both transforming growth factor-β and bone morphogenetic protein signalling pathways upon traumatic brain injury restrains pro-inflammatory and boosts tissue reparatory responses of reactive astrocytes and microglia
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脑外伤后激活转化生长因子-β 和骨形态发生蛋白信号通路可抑制促炎症反应，并促进反应性星形胶质细胞和小胶质细胞的组织修复反应
DOI：
10.1093/braincomms/fcz028
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发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Sideras, Paschalis
中科院分区：
文献类型：
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作者：
Divolis, Georgios;Stavropoulos, Athanasios;Sideras, Paschalis
已发现创伤性脑损伤后转化生长因子-β超家族的各种配体和受体上调;然而，该信号系统在脑损伤病理生理学中的作用尚未完全表征。为了解决这个问题，我们利用急性刺伤脑损伤模型，以证明转化生长因子-β超家族系统激活的标志，如磷酸化Smads的水平，转化生长因子-β和骨形态发生蛋白途径的配体和靶基因，在损伤组织中上调。使用骨形态发生蛋白反应报告小鼠模型，我们发现，激活的骨形态发生蛋白信号通路主要涉及星形胶质细胞划分的伤口面积。通过用骨形态发生蛋白-4或转化生长因子-β 1处理纯化的反应性星形胶质细胞和小胶质细胞，并表征其转录谱的变化，间接获得了关于转化生长因子-β超家族激活在受损组织内胶质细胞中的潜在作用的见解。星形胶质细胞对两种配体的反应具有相当大的重叠性，而小胶质细胞选择性地对转化生长因子β 1作出反应。星形胶质细胞中的转化生长因子-β 1和/或骨形态发生蛋白-4上调了对组织损伤和血脑屏障修复至关重要的新途径，如胆固醇生物合成和转运的激活、轴突导向和细胞外基质成分的产生。此外，星形胶质细胞中的配体和小胶质细胞中的转化生长因子-β 1分别将反应性胶质细胞的表型向抗炎和组织修复“A2”样和“M0/M2”样表型转移。在伤口区域内确认了体外调制途径和“A2”样星形胶质细胞标记物的选定关键组分的表达增加，表明这些过程也可以通过转化生长因子-β和/或骨形态发生蛋白介导的信号传导的综合作用原位调制。总的来说，我们的研究提供了一个全面的比较分析转化生长因子-β超家族信号在反应性星形胶质细胞和小胶质细胞，并指向一个关键的作用，转化生长因子-β和骨形态发生蛋白途径在调节炎症和脑损伤修复功能的激活胶质细胞。
Various ligands and receptors of the transforming growth factor-beta superfamily have been found upregulated following traumatic brain injury; however, the role of this signalling system in brain injury pathophysiology is not fully characterized. To address this, we utilized an acute stab wound brain injury model to demonstrate that hallmarks of transforming growth factor-beta superfamily system activation, such as levels of phosphorylated Smads, ligands and target genes for both transforming growth factor-beta and bone morphogenetic protein pathways, were upregulated within injured tissues. Using a bone morphogenetic protein-responsive reporter mouse model, we showed that activation of the bone morphogenetic protein signalling pathway involves primarily astrocytes that demarcate the wound area. Insights regarding the potential role of transforming growth factor-beta superfamily activation in glia cells within the injured tissues were obtained indirectly by treating purified reactive astrocytes and microglia with bone morphogenetic protein-4 or transforming growth factor-beta 1 and characterizing changes in their transcriptional profiles. Astrocytes responded to both ligands with considerably overlapping profiles, whereas, microglia responded selectively to transforming growth factor-beta 1. Novel pathways, crucial for repair of tissue-injury and blood-brain barrier, such as activation of cholesterol biosynthesis and transport, production of axonal guidance and extracellular matrix components were upregulated by transforming growth factor-beta 1 and/or bone morphogenetic protein-4 in astrocytes. Moreover, both ligands in astrocytes and transforming growth factor-beta 1 in microglia shifted the phenotype of reactive glia cells towards the anti-inflammatory and tissue reparatory 'A2'-like and 'M0/M2'-like phenotypes, respectively. Increased expression of selected key components of the in vitro modulated pathways and markers of 'A2'-like astrocytes was confirmed within the wound area, suggesting that these processes could also be modulated in situ by the integrated action of transforming growth factor-beta and/or bone morphogenetic protein-mediated signalling. Collectively, our study provides a comprehensive comparative analysis of transforming growth factor-beta superfamily signalling in reactive astrocytes and microglia and points towards a crucial role of both transforming growth factor-beta and bone morphogenetic protein pathways in modulating the inflammatory and brain injury reparatory functions of activated glia cells.