CERVO Brain Research Centre, Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec City, QC G1J 2G3, Canada.
CHU de Québec, Department of Medicine, Université Laval, Québec City, QC G1J 1Z4, Canada.
Int J Mol Sci. 2023 Mar 7;24(6):5065. doi: 10.3390/ijms24065065.
Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune-metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune-metabolic homeostasis in ALS.
肌萎缩侧索硬化症（ALS）是一种临床表现高度异质性的疾病，患者的生存率从数月到数十年不等。有证据表明，全身免疫反应失调可能发挥作用并影响疾病进展。在这里，我们测量了 62 种不同的免疫/代谢介质在散发性肌萎缩侧索硬化症（sALS）患者的血浆中的水平。我们表明，在蛋白水平上，大多数免疫介质，包括代谢传感器瘦素，在 sALS 患者和两种疾病动物模型的血浆中均显著降低。接下来，我们发现，一部分进展迅速的 ALS 患者会出现一种独特的血浆免疫代谢分子特征，其特点是可溶性肿瘤坏死因子受体 II（sTNF-RII）和趋化因子（C-C 基序）配体 16（CCL16）的差异增加，而瘦素水平进一步降低，这种变化主要发生在男性患者中。与体内发现一致，将 sALS 患者的血浆和/或 sTNF-RII 单独暴露于人脂肪细胞中，会导致瘦素产生/稳态的显著失调，并与 AMP 激活蛋白激酶（AMPK）磷酸化的显著增加相关。相反，用 AMPK 抑制剂处理可恢复人脂肪细胞中的瘦素产生。总之，这项研究提供了 sALS 中独特的血浆免疫谱的证据，该免疫谱影响脂肪细胞的功能和瘦素信号。此外，我们的结果表明，靶向脂肪细胞中的 sTNF-RII/AMPK/leptin 通路可能有助于恢复 ALS 中的评估免疫代谢平衡。
