Neuroinflammation plays a key role in exacerbating dopaminergic neuron (DAN) loss in Parkinson’s disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes, and DAN loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that alleviated DAN loss in mice overexpressing the human SNCA gene in the substantia nigra. Single-cell transcriptomics revealed that IL-10 induced the emergence of a molecularly distinct microglial cell state, enriched in markers of cell activation with enhanced expression of prophagocytic pathways. IL-10 promoted microglial phagocytotic and clearance activities in vitro and reduced αSYN aggregate burden in the nigral area in mice overexpressing SNCA . Furthermore, IL-10 stimulated the differentiation of CD4 + T lymphocytes into active T regulatory cells and promoted inhibitory characteristics in CD8 + T cells. In summary, our results show that local and microglia-specific IL-10 transduction elicited strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity that was associated with DAN survival. These results offer insights into the therapeutic benefits of IL-10 and showcase a promising gene delivery approach that could minimize undesired side effects.

中文翻译：

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小胶质细胞特异性 IL-10 基因传递抑制帕金森病小鼠模型的神经炎症和神经变性


神经炎症在加剧帕金森病 (PD) 多巴胺能神经元 (DAN) 损失方面发挥着关键作用。然而，鉴于在像大脑这样难以接近的器官中发生的先天性免疫反应和适应性免疫反应之间复杂的相互作用，如何有效地使这种免疫反应正常化仍然悬而未决。在这项研究中，我们发现了几种常用的由各种病理触发因素产生的 PD 小鼠模型中，神经炎症、脑实质淋巴细胞和 DAN 丢失之间存在一致的相关性。我们验证了一种针对小胶质细胞特异性表达白细胞介素 10 (IL-10) 的病毒治疗方法，以选择性减轻过度的炎症反应。我们发现，这种方法诱导了黑质局部 IL-10 的释放，从而减轻了黑质中过度表达人类 SNCA 基因的小鼠的 DAN 损失。单细胞转录组学显示，IL-10 诱导分子上独特的小胶质细胞状态的出现，富含细胞激活标记物，并增强前吞噬细胞通路的表达。 IL-10 在体外促进小胶质细胞吞噬和清除活性，并减少过度表达 SNCA 的小鼠黑质区的 αSYN 聚集负担。此外，IL-10 刺激 CD4 + T 淋巴细胞分化为活性 T 调节细胞，并促进 CD8 + T 细胞的抑制特性。总之，我们的结果表明，局部和小胶质细胞特异性的 IL-10 转导在黑质组织中引发了强烈的免疫调节，并增强了与 DAN 存活相关的淋巴细胞毒性的抑制。这些结果提供了对 IL-10 治疗益处的深入了解，并展示了一种有前途的基因递送方法，可以最大限度地减少不良副作用。