Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes
BACKGROUND Fasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODS We explored the underlying biology in myeloid cells from healthy volunte...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-03-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI139828 |
| _version_ | 1811237952306544640 |
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| author | Jing Wu Komudi Singh Amy Lin Allison M. Meadows Kaiyuan Wu Vivian Shing Maximilian Bley Shahin Hassanzadeh Rebecca D. Huffstutler Mark S. Schmidt Luz P. Blanco Rong Tian Charles Brenner Mehdi Pirooznia Mariana J. Kaplan Michael N. Sack |
| author_facet | Jing Wu Komudi Singh Amy Lin Allison M. Meadows Kaiyuan Wu Vivian Shing Maximilian Bley Shahin Hassanzadeh Rebecca D. Huffstutler Mark S. Schmidt Luz P. Blanco Rong Tian Charles Brenner Mehdi Pirooznia Mariana J. Kaplan Michael N. Sack |
| author_sort | Jing Wu |
| collection | DOAJ |
| description | BACKGROUND Fasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODS We explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE).RESULTS RNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-β production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that NAD+ is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-β release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-β release.CONCLUSION We conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management.TRIAL REGISTRATION ClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDING This work was supported by the NHLBI and NIAMS Intramural Research divisions. |
| first_indexed | 2024-04-12T12:32:16Z |
| format | Article |
| id | doaj.art-a5920c2523044c81b76b48c3c78216ac |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-12T12:32:16Z |
| publishDate | 2022-03-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-a5920c2523044c81b76b48c3c78216ac2022-12-22T03:32:59ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-03-011325Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytesJing WuKomudi SinghAmy LinAllison M. MeadowsKaiyuan WuVivian ShingMaximilian BleyShahin HassanzadehRebecca D. HuffstutlerMark S. SchmidtLuz P. BlancoRong TianCharles BrennerMehdi PiroozniaMariana J. KaplanMichael N. SackBACKGROUND Fasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODS We explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE).RESULTS RNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-β production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that NAD+ is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-β release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-β release.CONCLUSION We conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management.TRIAL REGISTRATION ClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDING This work was supported by the NHLBI and NIAMS Intramural Research divisions.https://doi.org/10.1172/JCI139828InflammationMetabolism |
| spellingShingle | Jing Wu Komudi Singh Amy Lin Allison M. Meadows Kaiyuan Wu Vivian Shing Maximilian Bley Shahin Hassanzadeh Rebecca D. Huffstutler Mark S. Schmidt Luz P. Blanco Rong Tian Charles Brenner Mehdi Pirooznia Mariana J. Kaplan Michael N. Sack Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes The Journal of Clinical Investigation Inflammation Metabolism |
| title | Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes |
| title_full | Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes |
| title_fullStr | Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes |
| title_full_unstemmed | Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes |
| title_short | Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes |
| title_sort | boosting nad blunts tlr4 induced type i ifn in control and systemic lupus erythematosus monocytes |
| topic | Inflammation Metabolism |
| url | https://doi.org/10.1172/JCI139828 |
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