Xie Yangzhi, Chen Jiacheng, Xu Sicong, Cheng Oumei
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Department of Intensive Care Unit, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421002, China.
Int Immunopharmacol. 2025 Feb 20;148:114104. doi: 10.1016/j.intimp.2025.114104. Epub 2025 Jan 24.
Circulating levels of the female hormone estrogen has been associated with the development of Parkinson's disease (PD), although the underlying mechanism remains unclear. Immune homeostasis mediated by peripheral regulatory T cells (Treg) is a crucial factor in PD. The aim of this study was to explore the effects of estrogen deficiency on neuroinflammation and neurodegeneration in a rodent model of PD, with particular reference to Treg.
Estrogen deficiency was established in a mouse model by bilateral ovariectomy (OVX). PD was modeled by the injection of LPS into the striatum. Motor performance was assessed in each experimental group. Dopaminergic degeneration was evaluated using tyrosine-hydroxylase (Th) immunohistochemical staining of the substantia nigra (SN) and striatum. Dopamine and dopamine metabolite levels in the striatum were also evaluated, together with the infiltration of CD4 T cells into the SN. Neuroinflammation was assessed by evaluating the mRNA level of microglial and M1/M2 phenotype markers, as well as the abundance of pro-inflammatory cytokines in the midbrain. The frequency of peripheral Treg cells was evaluated using flow cytometry.
OVX prior to LPS injection markedly aggravated neurodegeneration, neuroinflammation, motor performance, and CD4 T cell infiltration compared to the LPS-only group. Estradiol treatment or activation of the G protein-coupled estrogen receptor (GPER) in OVX mice prior to LPS injection induced functional improvement and reduced the levels of neurodegeneration, neuroinflammation, and CD4 T cell infiltration. OVX prior to LPS injection also led to a decreased frequency of Treg compared to the LPS-only group. Moreover, estradiol treatment or GPER activation of OVX mice prior to LPS injection significantly increased the Treg frequency. Antibody-mediated depletion of Treg after GPER activation counteracted the ability of GPER to alleviate neurodegeneration, CD4 T cell infiltration, the release of pro-inflammatory cytokines, and motor performance in the PD model.
Estrogen deficiency can disrupt Treg-mediated immune homeostasis and thus further aggravate microglial inflammation and dopaminergic degeneration in PD model. The effects of estrogen on Treg may be partially mediated by GPER signaling, and thus GPER is a promising target for PD, especially in estrogen-deficient women.
女性激素雌激素的循环水平与帕金森病（PD）的发生有关，但其潜在机制尚不清楚。外周调节性T细胞（Treg）介导的免疫稳态是PD中的一个关键因素。本研究的目的是探讨雌激素缺乏对PD啮齿动物模型中神经炎症和神经退行性变的影响，尤其涉及Treg。
通过双侧卵巢切除术（OVX）在小鼠模型中建立雌激素缺乏状态。通过向纹状体注射脂多糖（LPS）建立PD模型。评估每个实验组的运动性能。使用酪氨酸羟化酶（Th）免疫组化染色评估黑质（SN）和纹状体中的多巴胺能神经元变性。还评估了纹状体中的多巴胺和多巴胺代谢物水平，以及CD4 T细胞向SN的浸润情况。通过评估小胶质细胞和M1/M2表型标志物的mRNA水平以及中脑中促炎细胞因子的丰度来评估神经炎症。使用流式细胞术评估外周Treg细胞的频率。
与仅注射LPS的组相比，在注射LPS之前进行OVX显著加重了神经退行性变、神经炎症、运动性能和CD4 T细胞浸润。在注射LPS之前，对OVX小鼠进行雌二醇治疗或激活G蛋白偶联雌激素受体（GPER）可诱导功能改善，并降低神经退行性变、神经炎症和CD4 T细胞浸润水平。与仅注射LPS的组相比，在注射LPS之前进行OVX还导致Treg频率降低。此外，在注射LPS之前，对OVX小鼠进行雌二醇治疗或GPER激活可显著增加Treg频率。在GPER激活后，抗体介导的Treg耗竭抵消了GPER减轻PD模型中神经退行性变、CD4 T细胞浸润、促炎细胞因子释放和运动性能的能力。
雌激素缺乏可破坏Treg介导的免疫稳态，从而进一步加重PD模型中的小胶质细胞炎症和多巴胺能神经元变性。雌激素对Treg的作用可能部分由GPER信号介导，因此GPER是PD的一个有前景的靶点，尤其是在雌激素缺乏的女性中。
