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

Kim Han; Komudi Singh; Allison M Meadows; Rahul Sharma; Shahin Hassanzadeh; Jing Wu; Haley Goss-Holmes; Rebecca D Huffstutler; Heather L Teague; Nehal N Mehta; Julian L Griffin; Rong Tian; Javier Traba; Michael N Sack

doi:10.1016/j.xcrm.2023.101157

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

Kim Han, Komudi Singh, Allison M Meadows, Rahul Sharma, Shahin Hassanzadeh, Jing Wu, Haley Goss-Holmes, Rebecca D Huffstutler, Heather L Teague, Nehal N Mehta, Julian L Griffin, Rong Tian, Javier Traba, Michael N Sack^* (Corresponding Author)

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	101157
Number of pages	23
Journal	Cell reports. Medicine
Volume	4
Issue number	9
Early online date	19 Sept 2023
DOIs	https://doi.org/10.1016/j.xcrm.2023.101157
Publication status	Published - 19 Sept 2023

Bibliographical note

Acknowledgments
We thank Myron Waclawiw of the NHLBI Biostatistics Branch for assistance with the clinical protocol design, Chromadex for supplying NR and matching placebo capsules for the in vivo study and NR powder for the cell culture studies, and an NIH Bench-to-Bedside award for supplemental funding. We additionally thank Dr. Nina Klimova, formerly of the NHLBI, and Dr. Yun-Wei A. Hsu for their support of the metabolomics analysis at the Northwest Metabolomics Research Center of the University of Washington (NIH grant 1S10OD021562-01). We thank and acknowledge the assistance of the NHLBI DNA Sequencing and Genomics Core in performing the RNA library sequencing and Dr. Pradeep Dagur in the NHLBI Flow Cytometry Core for performing the immunophenotyping. Trial registration was as follows: ClinicalTrials.gov: NCT01934660, NCT02812238, and NCT01143454 and NIH Clinical Center blood bank (ClinicalTrials.gov: NCT00001846). This work was supported by the NHLBI Division of Intramural Research (ZIA-HL005102 to M.N.S.), NIH Bench-to-Bedside award (HL-129510-04S1 to M.N.S. and R.T.) and the NIH Office of Dietary Supplements (J.T.), the Spanish Ministry of Science and Innovation (RYC2018-026050-I and PID2019-105665RA-I00 to J.T.), and the UK MRC (MR/P011705/2 and UKDRI-5002 to J.L.G.; MAP UK).

Keywords

Humans
NAD/metabolism
Sequestosome-1 Protein/metabolism
Antioxidants/metabolism
NF-E2-Related Factor 2/genetics
Oxidation-Reduction
Inflammation/drug therapy

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Han_etal_CRM_Boosting_NAD_Preferentially_VoR
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Han, K., Singh, K., Meadows, A. M., Sharma, R., Hassanzadeh, S., Wu, J., Goss-Holmes, H., Huffstutler, R. D., Teague, H. L., Mehta, N. N., Griffin, J. L., Tian, R., Traba, J., & Sack, M. N. (2023). Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects. Cell reports. Medicine, 4(9), 101157. https://doi.org/10.1016/j.xcrm.2023.101157

Han, K, Singh, K, Meadows, AM, Sharma, R, Hassanzadeh, S, Wu, J, Goss-Holmes, H, Huffstutler, RD, Teague, HL, Mehta, NN, Griffin, JL, Tian, R, Traba, J & Sack, MN 2023, 'Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects', Cell reports. Medicine, vol. 4, no. 9, pp. 101157. https://doi.org/10.1016/j.xcrm.2023.101157

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

abstract = "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.",

keywords = "Humans, NAD/metabolism, Sequestosome-1 Protein/metabolism, Antioxidants/metabolism, NF-E2-Related Factor 2/genetics, Oxidation-Reduction, Inflammation/drug therapy",

author = "Kim Han and Komudi Singh and Meadows, {Allison M} and Rahul Sharma and Shahin Hassanzadeh and Jing Wu and Haley Goss-Holmes and Huffstutler, {Rebecca D} and Teague, {Heather L} and Mehta, {Nehal N} and Griffin, {Julian L} and Rong Tian and Javier Traba and Sack, {Michael N}",

note = "Acknowledgments We thank Myron Waclawiw of the NHLBI Biostatistics Branch for assistance with the clinical protocol design, Chromadex for supplying NR and matching placebo capsules for the in vivo study and NR powder for the cell culture studies, and an NIH Bench-to-Bedside award for supplemental funding. We additionally thank Dr. Nina Klimova, formerly of the NHLBI, and Dr. Yun-Wei A. Hsu for their support of the metabolomics analysis at the Northwest Metabolomics Research Center of the University of Washington (NIH grant 1S10OD021562-01). We thank and acknowledge the assistance of the NHLBI DNA Sequencing and Genomics Core in performing the RNA library sequencing and Dr. Pradeep Dagur in the NHLBI Flow Cytometry Core for performing the immunophenotyping. Trial registration was as follows: ClinicalTrials.gov: NCT01934660, NCT02812238, and NCT01143454 and NIH Clinical Center blood bank (ClinicalTrials.gov: NCT00001846). This work was supported by the NHLBI Division of Intramural Research (ZIA-HL005102 to M.N.S.), NIH Bench-to-Bedside award (HL-129510-04S1 to M.N.S. and R.T.) and the NIH Office of Dietary Supplements (J.T.), the Spanish Ministry of Science and Innovation (RYC2018-026050-I and PID2019-105665RA-I00 to J.T.), and the UK MRC (MR/P011705/2 and UKDRI-5002 to J.L.G.; MAP UK).",

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T1 - Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects

AU - Han, Kim

AU - Singh, Komudi

AU - Meadows, Allison M

AU - Sharma, Rahul

AU - Hassanzadeh, Shahin

AU - Wu, Jing

AU - Goss-Holmes, Haley

AU - Huffstutler, Rebecca D

AU - Teague, Heather L

AU - Mehta, Nehal N

AU - Griffin, Julian L

AU - Tian, Rong

AU - Traba, Javier

AU - Sack, Michael N

N1 - Acknowledgments We thank Myron Waclawiw of the NHLBI Biostatistics Branch for assistance with the clinical protocol design, Chromadex for supplying NR and matching placebo capsules for the in vivo study and NR powder for the cell culture studies, and an NIH Bench-to-Bedside award for supplemental funding. We additionally thank Dr. Nina Klimova, formerly of the NHLBI, and Dr. Yun-Wei A. Hsu for their support of the metabolomics analysis at the Northwest Metabolomics Research Center of the University of Washington (NIH grant 1S10OD021562-01). We thank and acknowledge the assistance of the NHLBI DNA Sequencing and Genomics Core in performing the RNA library sequencing and Dr. Pradeep Dagur in the NHLBI Flow Cytometry Core for performing the immunophenotyping. Trial registration was as follows: ClinicalTrials.gov: NCT01934660, NCT02812238, and NCT01143454 and NIH Clinical Center blood bank (ClinicalTrials.gov: NCT00001846). This work was supported by the NHLBI Division of Intramural Research (ZIA-HL005102 to M.N.S.), NIH Bench-to-Bedside award (HL-129510-04S1 to M.N.S. and R.T.) and the NIH Office of Dietary Supplements (J.T.), the Spanish Ministry of Science and Innovation (RYC2018-026050-I and PID2019-105665RA-I00 to J.T.), and the UK MRC (MR/P011705/2 and UKDRI-5002 to J.L.G.; MAP UK).

PY - 2023/9/19

Y1 - 2023/9/19

N2 - 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.

AB - 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.

KW - Humans

KW - NAD/metabolism

KW - Sequestosome-1 Protein/metabolism

KW - Antioxidants/metabolism

KW - NF-E2-Related Factor 2/genetics

KW - Oxidation-Reduction

KW - Inflammation/drug therapy

U2 - 10.1016/j.xcrm.2023.101157

DO - 10.1016/j.xcrm.2023.101157

M3 - Article

C2 - 37586364

SN - 2666-3791

VL - 4

SP - 101157

JO - Cell reports. Medicine

JF - Cell reports. Medicine

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

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