Boosting NAD+ blunts toll-like receptor-4 induced type-I interferon in control and systemic lupus erythematosus monocytes.

Fasting and NAD+-boosting compounds including NAD+ precursor nicotinamide riboside (NR) confer anti-inflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.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 subjects with systemic lupus erythematosus (SLE).RNA sequencing of unstimulated and lipopolysaccharide (LPS)-activated monocytes implicate NR in the regulation of autophagy and type I interferon signaling. In primary monocytes NR blunts LPS-induced IFNβ production and genetic or pharmacologic disruption of autophagy phenocopies this effect. Given NAD+ is a co-enzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased inosine level. Inosine supplementation similarly blunts autophagy and IFNβrelease. Finally, as SLE exhibits type I interferon dysregulation, we assessed the NR effect on SLE patient monocytes and found that NR reduces autophagy and interferon-β release.We conclude that NR, in an NAD+-dependent manner and in part via inosine-signaling, mediates suppression of autophagy and attenuates type I interferon in myeloid cells and identifies NR as a potential adjunct for SLE management.ClinicalTrails.gov registration numbers: NCT02812238, NCT00001846 and NCT00001372.This work was supported by the NHLBI and NIAMS Divisions of Intramural Research.