Oncostatin M (OSM) is an IL-6 family member which exerts neuroprotective and remyelination-promoting effects after damage to the central nervous system (CNS). However, the role of OSM in neuro-inflammation is poorly understood. Here, we investigated OSM’s role in pathological events important for the neuro-inflammatory disorder multiple sclerosis (MS). We show that OSM receptor (OSMRβ) expression is increased on circulating lymphocytes of MS patients, indicating their elevated responsiveness to OSM signalling. In addition, OSM production by activated myeloid cells and astrocytes is increased in MS brain lesions. In experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, OSMRβ-deficient mice exhibit milder clinical symptoms, accompanied by diminished T helper 17 (Th17) cell infiltration into the CNS and reduced BBB leakage. In vitro, OSM reduces BBB integrity by downregulating the junctional molecules claudin-5 and VE-cadherin, while promoting secretion of the Th17-attracting chemokine CCL20 by inflamed BBB-endothelial cells and reactive astrocytes. Using flow cytometric fluorescence resonance energy transfer (FRET) quantification, we found that OSM-induced endothelial CCL20 promotes activation of lymphocyte function-associated antigen 1 (LFA-1) on Th17 cells. Moreover, CCL20 enhances Th17 cell adhesion to OSM-treated inflamed endothelial cells, which is at least in part ICAM-1 mediated. Together, these data identify an OSM-CCL20 axis, in which OSM contributes significantly to BBB impairment during neuro-inflammation by inducing permeability while recruiting Th17 cells via enhanced endothelial CCL20 secretion and integrin activation. Therefore, care should be taken when considering OSM as a therapeutic agent for treatment of neuro-inflammatory diseases such as MS.

制瘤素 M (OSM) 是 IL-6 家族成员，在中枢神经系统 (CNS) 受损后发挥神经保护和髓鞘再生促进作用。然而，人们对 OSM 在神经炎症中的作用知之甚少。在这里，我们调查了 OSM 在对神经炎症性疾病多发性硬化症 (MS) 重要的病理事件中的作用。我们显示 OSM 受体 (OSMRβ) 表达在 MS 患者的循环淋巴细胞上增加，表明它们对 OSM 信号传导的反应性升高。此外，在 MS 脑损伤中，活化的骨髓细胞和星形胶质细胞产生的 OSM 增加。在实验性自身免疫性脑脊髓炎 (EAE)（一种 MS 的临床前模型）中，OSMRβ 缺陷小鼠表现出较轻的临床症状，伴随着 T 辅助细胞 17 (Th17) 细胞浸润到 CNS 的减少和 BBB 渗漏减少。在体外，OSM 通过下调连接分子 claudin-5 和 VE-cadherin 来降低 BBB 的完整性，同时促进发炎的 BBB 内皮细胞和反应性星形胶质细胞分泌 Th17 吸引趋化因子 CCL20。使用流式细胞仪荧光共振能量转移 (FRET) 量化，我们发现 OSM 诱导的内皮 CCL20 促进 Th17 细胞上淋巴细胞功能相关抗原 1 (LFA-1) 的激活。此外，CCL20 增强了 Th17 细胞对 OSM 处理的发炎内皮细胞的粘附，这至少部分是 ICAM-1 介导的。总之，这些数据确定了一个 OSM-CCL20 轴，其中 OSM 通过诱导通透性同时通过增强的内皮 CCL20 分泌和整合素激活募集 Th17 细胞，从而显着促进神经炎症期间的 BBB 损伤。所以，