Chiot and colleagues investigated whether peripheral macrophages play a role in amyotrophic lateral sclerosis (ALS) pathology, finding that macrophages along peripheral motor neuron axons react to neurodegeneration. Modifying reactive oxygen species (ROS) signaling in peripheral macrophages, using bone marrow cell replacement, reduces both macrophage and microglia inflammatory response, delays pathology and increases survival in ALS mouse models.