Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France.
Department of Neurological, Biomedical and Movement Science, University of Verona, Verona, Italy.
Nat Neurosci. 2020 Nov;23(11):1339-1351. doi: 10.1038/s41593-020-00718-z. Epub 2020 Oct 19.
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，在 ALS 模型小鼠和患者中，沿周围运动神经元轴突的巨噬细胞对神经退行性变有反应。在 ALS 小鼠中，外周髓样细胞浸润脊髓的程度有限，并且取决于疾病持续时间。使用细胞替代物靶向调节 ALS 小鼠外周髓样细胞中的活性氧途径，可以减少外周巨噬细胞和小胶质细胞的激活，延迟症状并延长存活时间。转录组学研究表明，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，巨噬细胞的时间变化突然，小胶质细胞的激活则是进行性的、单向的。修饰外周巨噬细胞可抑制促炎小胶质细胞的反应，并向神经元支持转变。因此，在外周修饰巨噬细胞有能力影响疾病进展，可能对 ALS 具有治疗价值。
