Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species
Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species
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DOI：
10.1152/ajpcell.00376.2021
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发表时间：
2022-04-01
影响因子：
5.5
通讯作者：
Kon, Shigeyuki
中科院分区：
文献类型：
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作者：
Honda, Machiko;Segawa, Tatsuya;Kon, Shigeyuki
细胞外基质蛋白肾连蛋白（Npnt），一种对肾脏发育至关重要的蛋白质，在自身免疫性实验性自身免疫性脑炎（EAE）小鼠中的血液水平升高，EAE小鼠是多发性硬化症的模型。我们发现用针对α 881整联蛋白结合位点的抗Npnt抗体（Npnt阻断抗体）治疗可抑制EAE的发展。硒转运蛋白硒蛋白P（SeP）被确定为一种新的Npnt结合伴侣。在EAE中，Npnt诱导SeP和谷胱甘肽过氧化物酶1（GPx 1）表达，随后在CD 4（+）T细胞中抑制活性氧（ROS）;这些变化被Npnt阻断抗体处理干扰，这也导致产生白细胞介素（IL）-17的CD 4（+）T辅助细胞（Th 17 s）的分化受到抑制，调节性T细胞（TcR）的分化升高。用ROS清除剂N-乙酰半胱氨酸（NAC）治疗EAE小鼠，阻断了Npnt阻断抗体诱导的Th 17分化减少和Treg分化增加。总之，Npnt和SeP之间的相互作用通过ROS水平调节Th 17/Treg平衡有助于EAE的发展。
Blood levels of the extracellular matrix protein nephronectin (Npnt), a protein critical for kidney development, are elevated in autoimmune experimental autoimmune encephalitis (EAE) mice, which are a model for multiple sclerosis. We found here that treatment with anti-Npnt antibody directed against the oc881 integrin-binding site (Npnt-blocking antibody) inhibits EAE development. The selenium transporter selenoprotein P (SeP) was identified as a novel Npnt-binding partner. In EAE, Npnt induced SeP and glutathione peroxidase 1 (GPx1) expression, followed by reactive oxygen species (ROS) inhibition in CD4(+) T cells; these changes were disturbed by Npnt-blocking antibody treatment, which also caused suppressed differentiation of interleukin (IL)-17-producing CD4(+) T-helper cells (Th17s) and elevated differentiation of regulatory T cells (Tregs). Treatment of EAE mice with the ROS scavenger N-acetyl cysteine (NAC) blocked the Npnt-blocking antibody-induced decrease in Th17 differentiation and increase in Treg differentiation. In conclusion, the interaction between Npnt and SeP contributes to EAE development by regulating the Th17/Treg balance via the ROS level.