Novel role of aquaporin-4 in CD4+CD25+T regulatory cell development and severity of Parkinson's disease
Novel role of aquaporin-4 in CD4+CD25+T regulatory cell development and severity of Parkinson's disease
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DOI：
10.1111/j.1474-9726.2011.00677.x
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发表时间：
2011-06-01
期刊：
影响因子：
7.8
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Chi, Ying;Fan, Yi;Hu, Gang
P>；Aquaporin-4(AQP4)在哺乳动物脑中高度表达，参与脑部疾病的病理生理过程，包括中风、肿瘤、感染、脑积水、癫痫和创伤性脑损伤。我们发现，与野生型(WT)小鼠相比，AQP4基因缺陷小鼠对1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)或脂多糖等刺激敏感。在MPTP诱导的帕金森病(PD)小鼠模型中，与WT小鼠相比，AQP4缺陷动物表现出更强大的小胶质细胞炎症反应和更严重的多巴胺能神经元(DNS)丢失。然而，少数研究调查了AQP4水平异常与免疫功能障碍的关系。在这里，我们首次报道了AQP4在小鼠胸腺、脾和淋巴结中的表达。此外，与WT小鼠相比，AQP4基因缺陷小鼠的CD4+CD25+调节性T细胞数量显著减少，这可能是由于胸腺生成受损所致，这可能是MPTP诱导的PD模型中黑质致密部小胶质细胞炎症反应失控和随后严重的DNS丢失的原因。这些新的发现表明，AQP4缺乏可能扰乱免疫抑制调节，导致免疫反应过度活跃，并可能导致帕金森病或其他免疫相关疾病的严重程度增加。
P>Aquaporin-4 (AQP4) is highly expressed in mammalian brains and is involved in the pathophysiology of cerebral disorders, including stroke, tumors, infections, hydrocephalus, epilepsy, and traumatic brain injury. We found that AQP4-deficient mice were hypersensitive to stimulations such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide compared to wild-type (WT) littermates. In a mouse model of MPTP-induced Parkinson's disease (PD), AQP4-deficient animals show more robust microglial inflammatory responses and more severe loss of dopaminergic neurons (DNs) compared with WT mice. However, a few studies have investigated the association of abnormal AQP4 levels with immune dysfunction. Here, for the first time, we report AQP4 expression in mouse thymus, spleen, and lymph nodes. Furthermore, the significantly lower numbers of CD4+ CD25+ regulatory T cells in AQP4-deficient mice compared to WT mice, perhaps resulting from impaired thymic generation, may be responsible for the uncontrolled microglial inflammatory responses and subsequent severe loss of DNs in the substantia nigra pars compacta in the MPTP-induced PD model. These novel findings suggest that AQP4 deficiency may disrupt immunosuppressive regulators, resulting in hyperactive immune responses and potentially contributing to the increased severity of PD or other immune-associated diseases.