NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity

NAD⁺ has emerged as an important cofactor that can rewire metabolism and link energy status with cellular immune response reprogramming, raising the possibility that an improved understanding of NAD⁺ immunometabolic function in neuroinflammation could be exploited therapeutically. We have now identified the enzymes NAMPT, CD38, and the transcription factor NFATC3 as critical nodes in regulating astrocyte pathogenicity and controlling experimental neuroinflammation. Importantly, we have corroborated these murine findings in human astrocytes and analysis of MS brain samples. Overall, our results describe the role of NAD⁺ metabolism in the local immune response in the CNS and reveal targetable mechanistic insights into how NAD⁺ immunometabolic signaling controls astrocyte activation and promotes CNS autoimmunity.