Chronic IL-21 drives neuroinflammation and promotes lipid accumulation in microglia.

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Hugo Oyamada, Yinzhi Ying, Sudhanshu Agrawal, Aizhu Liu, Veedamali S Subramanian, Cleonice Alves de Melo Bento, Anshu Agrawal
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Abstract

Neuroinflammation is a key contributor to the onset and progression of neurodegenerative diseases, driven by factors such as viral infections, autoimmune disorders, and peripheral inflammation. However, the mechanisms linking peripheral inflammation or viral infections to neuroinflammation remain poorly understood, limiting the development of effective therapies. Proinflammatory cytokines are implicated in these processes but their effects on brain cells, including microglia, remain insufficiently characterized. Here, we demonstrate that IL-21, a proinflammatory cytokine elevated in autoimmune disorders, chronic viral infections, and Alzheimer's disease, activates microglia and promotes lipid accumulation within these cells. Young, healthy mice injected with IL-21 to mimic chronic exposure exhibited increased proinflammatory cytokine levels and microglial activation in the brain. Notably, microglia in these mice displayed enhanced lipid accumulation, accompanied by upregulation of lipid uptake receptors such as CD36 and TREM-2. These findings were corroborated using the human microglial cell line HMC-3, where IL-21 exposure similarly induced lipid accumulation and increased expression of CD36 and ApoE. Mechanistic investigations revealed that IL-21 upregulates HIF-1α, a transcription factor critical for lipid metabolism and lipid droplet formation. Additionally, we observed elevated IL-21 levels in the circulation of elderly individuals compared to younger counterparts, with IL-21 increases associated with CMV seropositivity. Aged mouse brains mirrored the microglial lipid accumulation and activation patterns seen in IL-21-injected mice. In summary, we identify a novel IL-21-driven mechanism involving lipid accumulation in microglia that contributes to neuroinflammation.

慢性IL-21驱动神经炎症,促进小胶质细胞脂质积累。
神经炎症是神经退行性疾病发生和发展的关键因素,由病毒感染、自身免疫性疾病和外周炎症等因素驱动。然而,将外周炎症或病毒感染与神经炎症联系起来的机制仍然知之甚少,限制了有效治疗方法的发展。促炎细胞因子与这些过程有关,但其对包括小胶质细胞在内的脑细胞的影响尚未充分表征。在这里,我们证明了IL-21,一种在自身免疫性疾病、慢性病毒感染和阿尔茨海默病中升高的促炎细胞因子,激活小胶质细胞并促进这些细胞内的脂质积累。年轻、健康的小鼠注射IL-21来模拟慢性暴露,显示出促炎细胞因子水平和大脑小胶质细胞激活的增加。值得注意的是,这些小鼠的小胶质细胞表现出增强的脂质积累,伴随着CD36和TREM-2等脂质摄取受体的上调。这些发现在人类小胶质细胞系HMC-3中得到证实,IL-21暴露同样诱导脂质积累,增加CD36和ApoE的表达。机制研究表明,IL-21上调HIF-1α, HIF-1α是脂质代谢和脂滴形成的关键转录因子。此外,我们观察到与年轻人相比,老年人循环中IL-21水平升高,IL-21升高与巨细胞病毒血清阳性相关。老年小鼠的大脑反映了注射il -21小鼠的小胶质细胞脂质积累和激活模式。总之,我们确定了一种新的il -21驱动机制,涉及小胶质细胞中的脂质积累,有助于神经炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
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