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

• Published in: Cell reports. Medicine Vol. 4; no. 9; p. 101157
• Main Authors: Han, Kim, Singh, Komudi, Meadows, Allison M., Sharma, Rahul, Hassanzadeh, Shahin, Wu, Jing, Goss-Holmes, Haley, Huffstutler, Rebecca D., Teague, Heather L., Mehta, Nehal N., Griffin, Julian L., Tian, Rong, Traba, Javier, Sack, Michael N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.09.2023; Elsevier
• Subjects: Advanced Basic Science; Antioxidants - metabolism; arginine biosynthesis; CD4+ T cell; Humans; Inflammation - drug therapy; NAD - metabolism; NAD+ boosting; NF-E2-Related Factor 2 - genetics; nicotinamide riboside; nrf2; Oxidation-Reduction; psoriasis; Sequestosome-1 Protein - metabolism; Th17 cell; NAD+ boosting; nrf2; Th17 cell; psoriasis; CD4+ T cell; arginine biosynthesis; nicotinamide riboside; CD4 + T cell; NAD + boosting; CD4(+) T cell; NAD(+) boosting
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101157

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. [Display omitted] •How NAD+ boosting blunts inflammation is poorly understood•Integrated transcriptomics and metabolomics identify T cell regulatory pathways•NAD+ increases arginine and fumarate biosynthesis•These metabolites, via NRF2 signaling, blunt Th1 and Th17 immune responsiveness Han et al. investigated NAD+-boosting effects on inflammation and found that nicotinamide riboside supplementation blunts Th1 and Th17 immune responsiveness in healthy volunteers and in psoriasis. Bioinformatics analysis uncovers that NAD+ boosting, via arginine and fumarate biosynthesis, activates NRF2. This transactivates antioxidant regulatory programs that blunt adaptive immune cell inflammatory signaling.