Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.

Jing Wu,Kaiyuan Wu,Maximilian Bley,Charles Brenner,Komudi Singh,Allison M Meadows,Amy Lin,Luz P Blanco,Mehdi Pirooznia,Rebecca D Huffstutler,Vivian Shing,Mark S Schmidt,Mariana J Kaplan,Michael N Sack,Rong Tian,Shahin Hassanzadeh

doi:10.1172/jci139828

Abstract

BACKGROUNDFasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODSWe 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).RESULTSRNA-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.CONCLUSIONWe 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 REGISTRATIONClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDINGThis work was supported by the NHLBI and NIAMS Intramural Research divisions.

Highlights

Caloric restriction, intermittent fasting, time-restricted feeding and fasting mimetic diets confer immunomodulatory effects including amelioration of inflammatory diseases [1,2,3,4,5,6], blunting of the NLRP3 inflammasome, circulating cytokines and acute-phase reactant levels [7,8,9]
We explored the underlying biology in myeloid cells from healthy volunteers following in-vivo placebo or nicotinamide riboside (NR) administration and subsequently tested the findings in-vitro in monocytes extracted from subjects with systemic lupus erythematosus (SLE)
In particular circulating monocytes and tissue macrophages, are first responders in pathogen clearance through a range of actions that resolve inflammation and support tissue homeostasis. Given these emerging findings we proposed that employing unbiased strategies to explore the effect of NR on monocytes would be a useful approach to begin to understand the broader roles of NAD+ supplementation on circulating innate immune cell function

Summary

Introduction

Intermittent fasting, time-restricted feeding and fasting mimetic diets confer immunomodulatory effects including amelioration of inflammatory diseases [1,2,3,4,5,6], blunting of the NLRP3 inflammasome, circulating cytokines and acute-phase reactant levels [7,8,9]. Caloric restriction promotes homing of leucocytes to the bone marrow [16] Despite these observations, the direct roles of caloric load on circulating immune cell homeostasis and activation are not well explored [17]. Coronavirus infection was recently shown to induce an interferon response that depressed cellular NAD+ in a manner that was opposed by supporting NAD+ status [26] Given these findings, and the potential use of NAD+ booster NR as a therapeutic supplement, supports further study into the regulatory mechanisms underpinning the NR effect on immune cells. We conclude that NR, in an NAD+-dependent manner and in part via inosinesignaling, mediates suppression of autophagy and attenuates type I interferon in myeloid cells and identifies NR as a potential adjunct for SLE management.

Methods

Results

Conclusion