Neurons promote encephalitogenic CD4+ lymphocyte infiltration in experimental autoimmune encephalomyelitis
Neurons promote encephalitogenic CD4+ lymphocyte infiltration in experimental autoimmune encephalomyelitis
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DOI：
10.1038/s41598-020-64363-z
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发表时间：
2020-04
影响因子：
4.6
通讯作者：
Yuki Nakazato;Y. Fujita;M. Nakazato;T. Yamashita
中科院分区：
文献类型：
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作者：
Yuki Nakazato;Y. Fujita;M. Nakazato;T. Yamashita
多发性硬化症（MS）是一种中枢神经系统自身免疫性疾病，其特征在于神经炎症，导致脱髓鞘和轴突变性。实验性自身免疫性脑炎（EAE）是MS的一种动物模型，由Ca 2 +/钙调素依赖性蛋白激酶IIα（CaMKIIα）介导的神经元兴奋性毒性导致EAE的神经元损伤。我们在靶向EAE的小鼠模型中，使用在CaMKIIα启动子下由设计药物（DREADD）专门激活的抑制性设计受体来沉默兴奋性神经元的活性。神经元沉默可减轻EAE的临床疾病评分，减少靶病变中c-fos、Tnfα、Ccl 2和Ccr 2 mRNA的表达，阻止CD 4+淋巴细胞向神经元的迁移; Ccl 2shRNA治疗靶病变可抑制CD 4+淋巴细胞的迁移，减轻EAE的运动障碍。我们的研究结果表明，EAE中的神经元激活促进了CCR 2 + CD 4+淋巴细胞的迁移，并且抑制性DREADD引起的神经元沉默使疾病的临床和分子标志物更加明确。神经元CCL 2被认为参与促进淋巴细胞迁移。
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, leading to demyelination and axonal degeneration. Neuronal excitotoxity mediated by Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) results in neuronal damage in experimental autoimmune encephalitis (EAE), an animal model of MS. Here, we define a critical role of excitatory neurons in the pathogenesis of CD4+lymphocyte accumulation in EAE. We silenced the activity of excitatory neurons in a mouse model of targeted EAE using inhibitory designer receptors exclusively activated by designer drugs (DREADD) under a CaMKIIα promoter. Neuronal silencing mitigated clinical disease scores in EAE, reduced the expression ofc-fos, Tnfα,Ccl2, andCcr2mRNAs in targeted EAE lesions, and prevented the migration of CD4+lymphocytes towards neurons.Ccl2shRNA treatment of targeted EAE suppressed the migration of CD4+lymphocytes and alleviated the motor deficits of EAE. Our findings indicate that neuronal activation in EAE promotes the migration of CCR2+CD4+lymphocytes and that neuronal silencing with an inhibitory DREADD alleviates clinical and molecular markers of disease. Neuronal CCL2 is thought to be involved in promoting lymphocytes migration.