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Modifying macrophages at the periphery has the capacity to change microglial reactivity and increase ALS survival

ABSTRACT: Microglia and peripheral macrophages, combined, have been implicated in the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but without discriminating their respective roles. We now show that macrophages along peripheral motor neuron axons of ALS mice and patients react to neurodegeneration. In ALS mice, peripheral myeloid cell infiltration into the spinal cord was limited and disease duration dependent. 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 ALS mouse survival. Transcriptomics revealed that sciatic nerve macrophages and microglia reacted very different to neurodegeneration, with abrupt temporal changes in macrophages and progressive, unidirectional activation in microglia. Modifying peripheral macrophages suppressed proinflammatory microglial responses, with a strong shift towards neuronal support. Thus, modifying macrophages at the periphery has the capacity to influence disease progression and is of therapeutic value for ALS.

ORGANISM(S): Mus musculus

PROVIDER: GSE156202 | GEO | 2020/10/19

REPOSITORIES: GEO

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