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 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-beta 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-beta 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-beta 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.

Automated summary

This study reveals that nicotinamide riboside (NR) can suppress autophagy and attenuate type I interferon (IFN-beta) release in myeloid cells, exerting anti-inflammatory effects. The mechanism of action involves NR's dependency on NAD(+) and its modulation of inosine signaling. These findings suggest NR as a potential adjunct for the management of systemic lupus erythematosus (SLE).