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.

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。我们现在表明，小鼠模型和 ALS 患者中沿外周运动神经元轴突的巨噬细胞对神经变性有反应。在 ALS 小鼠中，外周髓细胞浸润到脊髓中是有限的，并且取决于疾病持续时间。使用细胞替代对 ALS 小鼠外周髓细胞中的活性氧途径进行靶向基因调节，减少了外周巨噬细胞和小胶质细胞的活化，延迟了症状并提高了存活率。转录组学显示，坐骨神经巨噬细胞和小胶质细胞对神经退行性变的反应不同，巨噬细胞发生突然的时间变化，小胶质细胞进行性单向激活。修饰外周巨噬细胞可抑制促炎性小胶质细胞反应，并转向神经元支持。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。