Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Department of Pediatrics, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan.
Neuroscience. 2019 Dec 1;422:12-20. doi: 10.1016/j.neuroscience.2019.10.014. Epub 2019 Nov 6.
Oncostatin M (OSM) is a cytokine of the interleukin (IL)-6 family members. It induces blood-brain barrier (BBB) dysfunction by activating Janus-activated kinase (JAK) and signal transducer and activator of transcription (STAT) 3 pathways in brain endothelial cells. Brain pericytes located around microvessels are one of the BBB constituents. Pericytes work as a boundary surface between the blood circulation and brain parenchyma, and their functions are altered under pathophysiological conditions, leading to BBB dysregulation. However, it remains unknown whether pericytes are associated with OSM-induced BBB dysfunction. We demonstrated that pericyte exposure to OSM (100 ng/mL) elevated phosphorylation of STAT3, a main OSM signaling pathway, and that pericytes expressed OSM receptors (OSMRs) including OSMRβ and glycoprotein 130. These results suggest that pericytes are able to respond to OSM. To determine the effects of OSM-reactive pericytes on BBB functions, rat brain endothelial cell (RBEC) monolayers were cultured with OSM-treated pericytes. The presence of pericytes exposed to 100 ng/mL of OSM for 48 h aggravated both the elevated permeability to sodium fluorescein and the lowered transendothelial electrical resistance which were induced by OSM in RBECs. This OSM-reactive pericyte-induced aggravation of lowered RBEC barrier function was reversed by ruxolitinib, a JAK inhibitor. These findings suggest that activated JAK/STAT3 signaling in pericytes contributes to OSM-produced BBB breakdown. Thus, OSM-reactive pericytes may have to be considered a characteristic machinery in the formation and progression of BBB breakdown under pathological conditions associated with increased OSM levels.
肿瘤坏死因子样弱诱导剂（OSM）是白细胞介素（IL）-6 家族成员的细胞因子。它通过激活脑内皮细胞中的 Janus 激活激酶（JAK）和信号转导子和转录激活子（STAT）3 途径来诱导血脑屏障（BBB）功能障碍。位于微血管周围的脑周细胞是 BBB 的组成部分之一。周细胞作为血液循环和脑实质之间的边界表面，其功能在病理生理条件下发生改变，导致 BBB 失调。然而，目前尚不清楚周细胞是否与 OSM 诱导的 BBB 功能障碍有关。我们证明，周细胞暴露于 OSM（100ng/mL）会增加 STAT3 的磷酸化，这是 OSM 的主要信号通路，并且周细胞表达 OSM 受体（OSMRs），包括 OSMRβ和糖蛋白 130。这些结果表明周细胞能够对 OSM 做出反应。为了确定对 OSM 有反应的周细胞对 BBB 功能的影响，用 OSM 处理的周细胞培养大鼠脑内皮细胞（RBEC）单层。在存在暴露于 100ng/mL OSM 48 小时的周细胞的情况下，OSM 在 RBEC 中诱导的对荧光素钠的通透性增加和跨内皮电阻降低加剧。这种 OSM 反应性周细胞诱导的 RBEC 屏障功能降低的加重被 JAK 抑制剂鲁索替尼逆转。这些发现表明，周细胞中激活的 JAK/STAT3 信号通路有助于 OSM 产生的 BBB 破裂。因此，在与 OSM 水平升高相关的病理条件下，激活的 OSM 反应性周细胞可能成为 BBB 破裂形成和进展的特征机制。
