Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects

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To evaluate whether nicotinamide adenine dinucleotide-positive (NAD + ) boosting modulates adaptive immunity, primary CD4 + T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts interferon γ (IFNγ) and interleukin (IL)-17 secretion with greater effects on T helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates NR blunting of sequestosome 1 ( sqstm1/p62 )-coupled oxidative stress. NR administration increases sqstm1 and reduces reactive oxygen species (ROS) levels. Furthermore, NR activates nuclear factor erythroid 2-related factor 2 (Nrf2), and genetic knockdown of nrf2 and the Nrf2-dependent gene, sqstm1 , diminishes NR amelioratory effects. Metabolomics analysis identifies that NAD + boosting increases arginine and fumarate biosynthesis, and genetic knockdown of argininosuccinate lyase ameliorates NR effects on IL-17 production. Hence NR via amino acid metabolites orchestrates Nrf2 activation, augments CD4 + T cell antioxidant defenses, and attenuates Th17 responsiveness. Oral NR supplementation in healthy volunteers similarly increases serum arginine, sqstm1 , and antioxidant enzyme gene expression and blunts Th17 immune responsiveness, supporting evaluation of NAD + boosting in CD4 + T cell-linked inflammation.

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