Department of Pathology, Stanford University, Palo Alto, CA, USA.
Program in Immunology, Stanford University, Palo Alto, CA, USA.
Inflamm Res. 2024 Nov;73(11):1847-1857. doi: 10.1007/s00011-024-01935-z. Epub 2024 Aug 21.
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.
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.
Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45 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 + CD45 microglia and F4/80 + CD45 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.
These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.
先天免疫激活与肌萎缩侧索硬化症（ALS）的发病机制有关。然而，在 ALS 中控制这一生物能量需求过程的代谢途径仍难以捉摸。在这里，我们研究了固有免疫细胞的免疫代谢转化是否以及如何促进这种神经退行性疾病的实验模型中的疾病进展。
我们利用多维流式细胞术和整合代谢组学来描述 B6SJL-Tg（SOD1*G93A）1Gur/J 模型中循环和脊髓固有免疫细胞的免疫代谢表型（在运动功能障碍之前和之后的不同疾病阶段）。还进行了行为和生存分析，以确定能量调节化合物对固有免疫细胞代谢、炎症和疾病发展的影响。
循环炎症性 Ly6C+单核细胞和脊髓 F4/80+CD45 浸润物的时间协调积累发生在 SOD1-G93A 小鼠运动功能障碍之前。随后的代谢组学分析表明，这一现象伴随着脊髓炎症性 CD11b+细胞的糖酵解重编程，包括常驻 F4/80+CD45 小胶质细胞和 F4/80+CD45 浸润物。此外，ZLN005（一种 Ppargc1a 的小分子激活剂）通过抑制糖酵解，抑制脊髓 CD11b+细胞的炎症性糖酵解激活，增强运动功能，并延长 SOD1-G93A 小鼠的存活。
这些观察结果表明，调节固有免疫细胞的炎症性糖酵解重编程可能代表 ALS 的一种有前途的治疗方法。
