Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.
Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.
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DOI：
10.1172/jci139828
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发表时间：
2022-03-01
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影响因子：
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通讯作者：
Sack MN
中科院分区：
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作者：
Wu J;Singh K;Lin A;Meadows AM;Wu K;Shing V;Bley M;Hassanzadeh S;Huffstutler RD;Schmidt MS;Blanco LP;Tian R;Brenner C;Pirooznia M;Kaplan MJ;Sack MN
禁食和NAD+-增强化合物，包括NAD+前体烟酰胺核苷（NR），赋予抗抑郁作用。然而，其潜在机制和治疗潜力尚未完全确定。我们探索了体内安慰剂或NR给药后健康志愿者骨髓细胞中的潜在生物学，随后在体外从系统性红斑狼疮（SLE）患者中提取的单核细胞中测试了这些发现。未受刺激和LPS活化的单核细胞的RNA-Seq涉及NR在自噬和I型IFN信号传导的调节中。在原代单核细胞中，NR减弱LPS诱导的IFN-β产生，自噬的遗传或药理学破坏表型模仿了这种作用。鉴于NAD+是氧化还原反应中的辅酶，进行代谢组学并鉴定NR增加肌苷水平。肌苷补充类似地减弱自噬和IFN-β释放。最后，由于SLE表现出I型IFN失调，我们评估了NR对SLE患者单核细胞的作用，发现NR减少了自噬和IFN-β释放。我们的结论是，NR，在NAD+依赖的方式，部分通过肌苷信号，介导抑制骨髓细胞中的自噬和衰减I型IFN，我们确定NR作为一个潜在的辅助SLE管理。ClinicalTrials.gov注册号NCT 02812238、NCT 00001846和NCT 00001372。这项工作得到了NHLBI和NIAMS校内研究部门的支持。
Fasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory 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 patients with systemic lupus erythematosus (SLE). 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. 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. ClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372. This work was supported by the NHLBI and NIAMS Intramural Research divisions.