Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
Max Planck Institute of Psychiatry, Munich, Germany.
J Neurosci Res. 2020 Jul;98(7):1433-1456. doi: 10.1002/jnr.24611. Epub 2020 Mar 13.
Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood-brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB.
血管周星形胶质细胞突起（PAP）环绕脑内皮细胞（EC），调节紧密连接的增强，影响血脑屏障（BBB）的通透性。形态改变的星形胶质细胞可能会影响屏障特性，并引发脑部疾病的发生。然而，星形胶质细胞依赖性的这些事件的介质仍研究甚少。在这里，我们显示了一种药理学驱动的大鼠原代星形胶质细胞和脑 PAP 中生长/分化因子 15（GDF15）的表达和释放增加。已经表明 GDF15 对运动神经元具有营养特性，这促使我们假设它对星形胶质细胞也有类似的作用。事实上，它的表达和释放增加与体外星形胶质细胞和 PAP 的形态变化同时发生，表明 GDF15 对这些细胞以及相邻的 EC 具有调节作用。给予重组 GDF15 足以促进星形胶质细胞重塑，并增强体外 EC 之间的屏障特性，而其药理学遗传缺失则阻止了这些作用。我们在雄性高焦虑相关行为大鼠中验证了我们的发现，这是一种类似抑郁行为的动物模型，其 PAP 缩小与连接蛋白 claudin-5 的表达减少有关，而这些都可以通过药理学诱导的 GDF15 表达增加来恢复。因此，我们确定 GDF15 是星形胶质细胞来源的触发因子，可引发星形胶质细胞突起重塑，并增强 BBB 处紧密连接的增强。
