Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH, USA.
The Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH, USA.
J Neuroinflammation. 2021 Apr 20;18(1):98. doi: 10.1186/s12974-021-02146-7.
Multiple sclerosis (MS) is a debilitating neurological disease caused by autoimmune destruction of the myelin sheath. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for the pathogenesis of MS. We and others have previously demonstrated that IL-17 is critical for the pathogenesis of EAE. The concentration of IL-17 is significantly higher in the sera of MS patients than in healthy controls and correlates with disease activity. Moreover, anti-IL-17 neutralizing antibody demonstrated promising efficacy in a phase II trial in MS patients, further substantiating a key pathogenic role for IL-17 in MS. While Th17 and IL-17 are emerging as a bona fide drivers for neuroinflammation, it remains unclear what effector molecule executes the inflammatory tissue destruction in Th17-driven EAE.
By microarray analysis, we found STEAP4 is a downstream molecule of IL-17 signaling in EAE. We then used STEAP4 global knockout mice and STEAP4 conditional knockout mice to test its role in the pathogenesis of EAE.
Here, we report that the metalloreductase, STEAP4, is a key effector molecule that participates and contributes to the pathogenesis of Th17-mediated neuroinflammation in experimental autoimmune encephalomyelitis. STEAP4 knockout mice displayed delayed onset and reduced severity of EAE induced by active immunization. The reduced disease phenotype was not due to any impact of STEAP4 deficiency on myelin reactive T cells. In contrast, STEAP4 knockout mice were resistant to passively induced EAE, pointing to a role for STEAP4 in the effector stage of EAE. Notably, STEAP4 was only induced the spinal cord of EAE mice that received Th17 cells but not Th1 cells. Consistently, STEAP4 deficiency protected from only Th17 but not Th1-induced EAE. Finally, using Nestin-Cre STEAP4 mice, we showed that ablation of STEAP4 expression in the resident cells in the central nervous system attenuated disease severity in both active immunization and passive Th17 transfer-induced EAE.
In this study, we identified STEAP4 as a Th17-specific effector molecule that participates and contributes to the pathogenesis of neuroinflammation, thus potentially provide a novel target for MS therapy.
多发性硬化症（MS）是一种由自身免疫破坏髓鞘引起的使人虚弱的神经疾病。实验性自身免疫性脑脊髓炎（EAE）是一种广泛用于研究 MS 发病机制的动物模型。我们和其他人之前已经证明，IL-17 对于 EAE 的发病机制至关重要。MS 患者的血清中 IL-17 浓度明显高于健康对照者，并且与疾病活动度相关。此外，抗 IL-17 中和抗体在 MS 患者的 II 期试验中显示出有前景的疗效，进一步证实了 IL-17 在 MS 中的关键致病作用。虽然 Th17 和 IL-17 正在成为神经炎症的真正驱动因素，但尚不清楚在 Th17 驱动的 EAE 中哪种效应分子执行炎症性组织破坏。
通过微阵列分析，我们发现 STEAP4 是 EAE 中 IL-17 信号的下游分子。然后，我们使用 STEAP4 全局敲除小鼠和 STEAP4 条件敲除小鼠来测试其在 EAE 发病机制中的作用。
在这里，我们报告称，金属还原酶 STEAP4 是一种关键效应分子，参与并有助于 Th17 介导的实验性自身免疫性脑脊髓炎中的神经炎症发病机制。STEAP4 敲除小鼠表现出由主动免疫诱导的 EAE 发病延迟和严重程度降低。疾病表型的降低不是由于 STEAP4 缺乏对髓鞘反应性 T 细胞的任何影响。相反，STEAP4 敲除小鼠对被动诱导的 EAE 具有抗性，表明 STEAP4 在 EAE 的效应阶段起作用。值得注意的是，STEAP4 仅在接受 Th17 细胞而不是 Th1 细胞的 EAE 小鼠的脊髓中诱导。一致地，STEAP4 缺乏仅保护了由 Th17 而非 Th1 诱导的 EAE。最后，使用 Nestin-Cre STEAP4 小鼠，我们表明中枢神经系统中驻留细胞中 STEAP4 表达的缺失减轻了主动免疫和被动 Th17 转移诱导的 EAE 中的疾病严重程度。
在这项研究中，我们确定了 STEAP4 作为 Th17 特异性效应分子，参与并有助于神经炎症的发病机制，从而为 MS 治疗提供了一个新的潜在靶点。
