Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA.
Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA; Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK.
Cell Rep Med. 2023 Sep 19;4(9):101157. doi: 10.1016/j.xcrm.2023.101157. Epub 2023 Aug 15.
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.
为了评估烟酰胺腺嘌呤二核苷酸（NAD）的增强是否调节适应性免疫，我们将来自健康对照者和银屑病患者的原代 CD4 T 细胞暴露于载体或烟酰胺核糖（NR）补充剂中。NR 可抑制干扰素 γ（IFNγ）和白细胞介素（IL）-17 的分泌，对 T 辅助（Th）17 极化的影响更大。RNA 测序（RNA-seq）分析表明，NR 阻断了自噬相关蛋白 1（sqstm1/p62）偶联的氧化应激。NR 给药增加了 sqstm1 并降低了活性氧（ROS）水平。此外，NR 激活核因子红细胞 2 相关因子 2（Nrf2），Nrf2 和 Nrf2 依赖性基因 sqstm1 的基因敲低削弱了 NR 的改善作用。代谢组学分析表明，NAD 的增强增加了精氨酸和富马酸的生物合成，而精氨酸琥珀酸裂解酶的基因敲低减轻了 NR 对 IL-17 产生的影响。因此，NR 通过氨基酸代谢物协调 Nrf2 的激活，增强 CD4 T 细胞的抗氧化防御能力，并减弱 Th17 的反应性。健康志愿者口服 NR 补充剂同样会增加血清精氨酸、sqstm1 和抗氧化酶基因的表达，并减轻 Th17 免疫反应性，支持 NAD 增强在 CD4 T 细胞相关炎症中的评估。
