Center for Neuroimmunology & Neuroinfectious Diseases.
Departments of Medicine.
Curr Opin Neurol. 2023 Jun 1;36(3):207-213. doi: 10.1097/WCO.0000000000001151. Epub 2023 Apr 18.
Microglia, which arise from primitive myeloid precursors that enter the central nervous system (CNS) during early development, are the first responders to any perturbance of homeostasis. Although their activation has become synonymous with neurologic disease, it remains unclear whether microglial responses are the cause of or response to neuropathology. Here, we review new insights in the roles of microglia during CNS health and disease, including preclinical studies that transcriptionally profile microglia to define their functional states.
Converging evidence suggests that innate immune activation of microglia is associated with overlapping alterations in their gene expression profiles regardless of the trigger. Thus, recent studies examining neuroprotective microglial responses during infections and aging mirror those observed during chronic neurologic diseases, including neurodegeneration and stroke. Many of these insights derive from studies of microglial transcriptomes and function in preclinical models, some of which have been validated in human samples. During immune activation, microglia dismantle their homeostatic functions and transition into subsets capable of antigen presentation, phagocytosis of debris, and management of lipid homeostasis. These subsets can be identified during both normal and aberrant microglial responses, the latter of which may persist long-term. The loss of neuroprotective microglia, which maintain a variety of essential CNS functions, may therefore, in part, underlie the development of neurodegenerative diseases.
Microglia exhibit a high level of plasticity, transforming into numerous subsets as they respond to innate immune triggers. Chronic loss of microglial homeostatic functions may underlie the development of diseases with pathological forgetting.
小胶质细胞起源于原始髓样前体细胞，这些前体细胞在早期发育过程中进入中枢神经系统（CNS），是对任何内稳态失调的第一反应者。尽管它们的激活已成为神经疾病的代名词，但仍不清楚小胶质细胞的反应是神经病理学的原因还是结果。在这里，我们回顾了小胶质细胞在中枢神经系统健康和疾病中的作用的新见解，包括对小胶质细胞进行转录谱分析以定义其功能状态的临床前研究。
越来越多的证据表明，小胶质细胞的先天免疫激活与其基因表达谱的重叠改变有关，而与触发因素无关。因此，最近研究感染和衰老期间神经保护小胶质细胞反应的研究反映了在慢性神经疾病（包括神经退行性变和中风）中观察到的反应。这些见解中的许多来自于临床前模型中小胶质细胞转录组和功能的研究，其中一些在人类样本中得到了验证。在免疫激活期间，小胶质细胞破坏其稳态功能，并转变为能够进行抗原呈递、吞噬碎片和管理脂质稳态的亚群。这些亚群可以在正常和异常小胶质细胞反应期间被识别，后者可能长期存在。因此，神经保护性小胶质细胞的丧失，这些小胶质细胞维持着中枢神经系统的多种重要功能，可能是神经退行性疾病发展的部分原因。
小胶质细胞表现出高度的可塑性，在对先天免疫触发做出反应时转化为许多亚群。小胶质细胞稳态功能的慢性丧失可能是病理性遗忘疾病发展的基础。
