Zhao Weihua, Beers David R, Hooten Kristopher G, Sieglaff Douglas H, Zhang Aijun, Kalyana-Sundaram Shanker, Traini Christopher M, Halsey Wendy S, Hughes Ashley M, Sathe Ganesh M, Livi George P, Fan Guo-Huang, Appel Stanley H
Department of Neurology, Peggy and Gary Edwards ALS Laboratory, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston, Texas.
Department of Neurosurgery, University of Florida, Gainesville.
JAMA Neurol. 2017 Jun 1;74(6):677-685. doi: 10.1001/jamaneurol.2017.0357.
Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Patients with ALS have persistent peripheral and central inflammatory responses including abnormally functioning T cells and activated microglia. However, much less is known about the inflammatory gene profile of circulating innate immune monocytes in these patients.
To characterize the transcriptomics of peripheral monocytes in patients with ALS.
DESIGN, SETTING, AND PARTICIPANTS: Monocytes were isolated from peripheral blood of 43 patients with ALS and 22 healthy control individuals. Total RNA was extracted from the monocytes and subjected to deep RNA sequencing, and these results were validated by quantitative reverse transcription polymerase chain reaction.
The differential expressed gene signatures of these monocytes were identified using unbiased RNA sequencing strategy for gene expression profiling.
The demographics between the patients with ALS (mean [SD] age, 58.8 [1.57] years; 55.8% were men and 44.2% were women; 90.7% were white, 4.65% were Hispanic, 2.33% were black, and 2.33% were Asian) and control individuals were similar (mean [SD] age, 57.6 [2.15] years; 50.0% were men and 50.0% were women; 90.9% were white, none were Hispanic, none were black, and 9.09% were Asian). RNA sequencing data from negative selected monocytes revealed 233 differential expressed genes in ALS monocytes compared with healthy control monocytes. Notably, ALS monocytes demonstrated a unique inflammation-related gene expression profile, the most prominent of which, including IL1B, IL8, FOSB, CXCL1, and CXCL2, were confirmed by quantitative reverse transcription polymerase chain reaction (IL8, mean [SE], 1.00 [0.18]; P = .002; FOSB, 1.00 [0.21]; P = .009; CXCL1, 1.00 [0.14]; P = .002; and CXCL2, 1.00 [0.11]; P = .01). Amyotrophic lateral sclerosis monocytes from rapidly progressing patients had more proinflammatory DEGs than monocytes from slowly progressing patients.
Our data indicate that ALS monocytes are skewed toward a proinflammatory state in the peripheral circulation and may play a role in ALS disease progression, especially in rapidly progressing patients. This increased inflammatory response of peripheral immune cells may provide a potential target for disease-modifying therapy in patients with ALS.
肌萎缩侧索硬化症（ALS）是一种常见的成人发病的神经退行性疾病，其特征是上下运动神经元选择性丧失。ALS患者存在持续的外周和中枢炎症反应，包括功能异常的T细胞和活化的小胶质细胞。然而，对于这些患者循环固有免疫单核细胞的炎症基因谱了解较少。
表征ALS患者外周单核细胞的转录组学特征。
设计、设置和参与者：从43例ALS患者和22名健康对照者的外周血中分离单核细胞。从单核细胞中提取总RNA并进行深度RNA测序，这些结果通过定量逆转录聚合酶链反应进行验证。
使用无偏RNA测序策略对基因表达进行分析，以鉴定这些单核细胞的差异表达基因特征。
ALS患者（平均[标准差]年龄，58.8[1.57]岁；55.8%为男性，44.2%为女性；90.7%为白人，4.65%为西班牙裔，2.33%为黑人，2.33%为亚洲人）与对照个体的人口统计学特征相似（平均[标准差]年龄，57.6[2.15]岁；50.0%为男性，50.0%为女性；90.9%为白人，无西班牙裔，无黑人，9.09%为亚洲人）。来自阴性选择单核细胞的RNA测序数据显示，与健康对照单核细胞相比，ALS单核细胞中有233个差异表达基因。值得注意的是，ALS单核细胞表现出独特的炎症相关基因表达谱，其中最突出的包括IL1B、IL8、FOSB、CXCL1和CXCL2，通过定量逆转录聚合酶链反应得到证实（IL8，平均[标准误]，1.00[0.18]；P = 0.002；FOSB，1.00[0.21]；P = 0.00�；CXCL1，1.00[0.14]；P = 0.002；CXCL2，1.00[0.11]；P = 0.01）。快速进展患者的肌萎缩侧索硬化单核细胞比缓慢进展患者的单核细胞有更多的促炎差异表达基因。
我们的数据表明，ALS单核细胞在外周循环中倾向于促炎状态，可能在ALS疾病进展中起作用，尤其是在快速进展患者中。外周免疫细胞这种增加的炎症反应可能为ALS患者的疾病修饰治疗提供潜在靶点。
