Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival
Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival
复制标题
DOI：
10.1038/s41593-020-00718-z
复制
发表时间：
2020-10-19
影响因子：
25
通讯作者：
Boillee, Severine
中科院分区：
文献类型：
--
作者：
Chiot, Aude;Zaidi, Sakina;Boillee, Severine
ALS小鼠中位于沿着运动轴突的外周巨噬细胞与CNS小胶质细胞相比对神经变性的反应不同。修饰外周巨噬细胞抑制促炎性小胶质细胞反应，使其转向神经元支持。小胶质细胞和外周巨噬细胞都与肌萎缩侧索硬化症（ALS）有关，尽管它们各自的作用尚未确定。我们现在发现，巨噬细胞沿着周围运动神经元轴突在小鼠模型和ALS患者的神经变性反应。在ALS小鼠中，外周髓样细胞浸润到脊髓中是有限的，并且取决于疾病持续时间。ALS小鼠外周髓样细胞中活性氧途径的靶向基因调节，使用细胞替代，减少外周巨噬细胞和小胶质细胞活化，延迟症状并增加存活。转录组学显示坐骨神经巨噬细胞和小胶质细胞对神经变性的反应不同，巨噬细胞的突然时间变化和小胶质细胞的进行性单向激活。修饰外周巨噬细胞抑制促炎性小胶质细胞反应，并向神经元支持转变。因此，修饰外周巨噬细胞具有影响疾病进展的能力，并且可能对ALS具有治疗价值。
Peripheral macrophages located along motor axons react differently to neurodegeneration compared to CNS microglia in ALS mice. Modifying peripheral macrophages suppresses proinflammatory microglial responses, shifting them toward neuronal support.Microglia and peripheral macrophages have both been implicated in amyotrophic lateral sclerosis (ALS), although their respective roles have yet to be determined. We now show that macrophages along peripheral motor neuron axons in mouse models and patients with ALS react to neurodegeneration. In ALS mice, peripheral myeloid cell infiltration into the spinal cord was limited and depended on disease duration. Targeted gene modulation of the reactive oxygen species pathway in peripheral myeloid cells of ALS mice, using cell replacement, reduced both peripheral macrophage and microglial activation, delayed symptoms and increased survival. Transcriptomics revealed that sciatic nerve macrophages and microglia reacted differently to neurodegeneration, with abrupt temporal changes in macrophages and progressive, unidirectional activation in microglia. Modifying peripheral macrophages suppressed proinflammatory microglial responses, with a shift toward neuronal support. Thus, modifying macrophages at the periphery has the capacity to influence disease progression and may be of therapeutic value for ALS.