Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-11-01 Epub Date: 2024-08-21 DOI:10.1007/s00011-024-01935-z
Lewis Yu, Nancy Wu, Okmi Choi, Khoa Dinh Nguyen
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Abstract

Background: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.

Methods: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.

Results: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45hi infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45low microglia and F4/80 + CD45hi infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice.

Conclusions: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.

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抑制糖酵解重编程可抑制实验性肌萎缩侧索硬化症中先天性免疫介导的炎症。
背景:先天性免疫激活与肌萎缩性脊髓侧索硬化症(ALS)的发病机制有关。然而,管理 ALS 中这一需要大量生物能的过程的代谢途径仍未确定。在此,我们研究了先天性免疫细胞的免疫代谢转化是否以及如何在这种神经退行性疾病的实验模型中导致疾病进展:方法:我们利用多维流式细胞术和综合代谢组学表征了B6SJL-Tg(SOD1*G93A)1Gur/J ALS(SOD1-G93A)模型中循环和脊髓先天性免疫细胞在不同疾病阶段(运动功能障碍发生之前和之后)的免疫代谢表型。此外还进行了行为和生存分析,以确定能量调节化合物对先天性免疫细胞代谢、炎症和疾病发展的影响:结果:在SOD1-G93A小鼠运动功能障碍发生之前,循环炎性Ly6C +单核细胞和脊髓F4/80 + CD45hi浸润的时间协调积累。随后的代谢组学分析表明,这一现象伴随着脊髓炎症 CD11b + 细胞的糖酵解重编程,包括常驻的 F4/80 + CD45low 小胶质细胞和 F4/80 + CD45hi 浸润。此外,Ppargc1a 的小分子激活剂 ZLN005 对糖酵解的药理抑制抑制了脊髓 CD11b + 细胞的炎症性糖酵解激活,增强了 SOD1-G93A 小鼠的运动功能并延长了存活时间:这些观察结果表明,调节先天性免疫细胞的炎性糖酵解重编程可能是治疗 ALS 的一种很有前景的方法。
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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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