代谢重编程驱动的神经免疫调节：中枢神经系统疾病的关键机制和治疗机遇与挑战
Metabolic reprogramming-driven neuroimmunoregulation: Key mechanisms and therapeutic opportunities and challenges in central nervous system disorders.
摘要(中文译文)
中枢神经系统（CNS）疾病与免疫细胞和胶质细胞内的代谢失调存在根本性关联。本综述系统整合了免疫代谢重编程——涵盖葡萄糖、脂质和氨基酸代谢以及氧化磷酸化——在CNS驻留小胶质细胞、免疫调节性星形胶质细胞和外周浸润免疫细胞（T细胞、B细胞和中性粒细胞）中于阿尔茨海默病、帕金森病、多发性硬化和缺血性卒中中的研究进展。关键在于，我们并非将所有已报道的代谢改变视为同等确证，而是引入了一个证据透明性框架，系统区分支持数据的性质——从直接代谢通量测定（Seahorse、同位素示踪、脂质组学）和分子相关性指标，到遗传/药理学扰动、人组织验证以及模型特异性观察——使读者能够独立评估每项主要结论的证据强度。我们进一步将衰老作为一个积极的分析维度加以阐述，展示线粒体质量控制、脂质处理、氧化还原缓冲以及胶质-免疫交互中的年龄相关变化如何建立一种允许性基线，从而修饰疾病特异性的重编程轨迹。通过整合细胞间交互、神经炎症、血脑屏障完整性和氧化应激的分析，我们阐明了不同疾病间趋同与趋异的代谢机制。最后，我们批判性评估了靶向免疫代谢的治疗策略，强调共同的转化障碍，包括靶点选择性、血脑屏障穿透、阶段依赖性疗效以及通路多效性这一固有挑战。本综述为解读免疫代谢证据、弥合相关性发现与因果机制之间的差距以及指导未来CNS疾病假设驱动的治疗设计提供了一个具有概念基础的框架。
Abstract
Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Critically, rather than presenting all reported metabolic alterations as equivalently established, we introduce an evidence-transparency framework that systematically distinguishes the nature of supporting data-ranging from direct metabolic flux measurements (Seahorse, isotope tracing, lipidomics) and molecular correlates, to genetic/pharmacological perturbations, human tissue validation, and model-specific observations-enabling readers to independently assess the strength of each major conclusion. We further delineate aging as an active analytical dimension, demonstrating how age-related changes in mitochondrial quality control, lipid handling, redox buffering, and glial-immune crosstalk establish a permissive baseline that modifies disease-specific reprogramming trajectories. By integrating analyses of intercellular crosstalk, neuroinflammation, blood-brain barrier integrity, and oxidative stress, we illustrate both convergent and divergent metabolic mechanisms across diseases. Finally, we critically assess therapeutic strategies targeting immunometabolism, emphasizing shared translational obstacles including target selectivity, blood-brain barrier penetration, stage-dependent efficacy, and the inherent challenge of pathway pleiotropy. This review provides a conceptually grounded framework for interpreting immunometabolic evidence, navigating the gap between correlative findings and causal mechanisms, and guiding future hypothesis-driven therapeutic design for CNS disorders.
如何引用
AMA
Nan Li, Yuanyuan Wu, Huiyi Feng, Xuemin Jian, Zhi Yang, Xilian Wang, et al. Metabolic reprogramming-driven neuroimmunoregulation: Key mechanisms and therapeutic opportunities and challenges in central nervous system disorders.. Ageing research reviews. 2026; doi:10.1016/j.arr.2026.103291.
APA
Nan Li, Yuanyuan Wu, Huiyi Feng, Xuemin Jian, Zhi Yang, Xilian Wang, et al (2026). Metabolic reprogramming-driven neuroimmunoregulation: Key mechanisms and therapeutic opportunities and challenges in central nervous system disorders.. Ageing research reviews. https://doi.org/10.1016/j.arr.2026.103291
GB/T 7714
Nan Li, Yuanyuan Wu, Huiyi Feng, Xuemin Jian, Zhi Yang, Xilian Wang, et al. Metabolic reprogramming-driven neuroimmunoregulation: Key mechanisms and therapeutic opportunities and challenges in central nervous system disorders.[J]. Ageing research reviews, 2026 doi:10.1016/j.arr.2026.103291.
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