Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Clin Invest. 2012 Sep;122(9):3063-87. doi: 10.1172/JCI62636. Epub 2012 Aug 6.
Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.
肌萎缩侧索硬化症（ALS）是一种与神经元细胞死亡相关的进行性疾病，据认为涉及异常的免疫反应。在这里，我们研究了固有免疫在 ALS 小鼠模型中的作用。我们发现炎性单核细胞被激活，其向脊髓的逐渐募集，但不包括大脑，与神经元丢失有关。我们还发现随着疾病的进展，脊髓中的常驻小胶质细胞减少。在疾病发作之前，脾脏 Ly6Chi 单核细胞表达极化的巨噬细胞表型（M1 特征），包括趋化因子受体 CCR2 的水平增加。随着疾病发作的临近，小胶质细胞表达增加的 CCL2 和其他趋化相关分子，导致单核细胞通过脊髓衍生的小胶质细胞向中枢神经系统募集。用抗 Ly6C mAb 治疗可调节 Ly6Chi 单核细胞细胞因子谱，减少单核细胞向脊髓的募集，减少神经元丢失，并延长生存。在 ALS 患者中，类似的单核细胞（CD14+CD16-）表现出与在 ALS 小鼠模型中观察到的相似的 ALS 特异性 microRNA 炎症特征，将动物模型与人类疾病联系起来。因此，ALS 患者单核细胞的特征可以作为疾病阶段或进展的生物标志物。我们的结果表明，炎性单核细胞的募集在疾病进展中起着重要作用，调节这些细胞是一种潜在的治疗方法。
