The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China.
Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome "Tor Vergata", Rome, Italy.
Cell Mol Immunol. 2023 Oct;20(10):1171-1185. doi: 10.1038/s41423-023-01073-2. Epub 2023 Aug 14.
Mesenchymal stem/stromal cells (MSCs) possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders. This capacity is not innate but is activated or 'licensed' by inflammatory cytokines. The licensing mechanism remains unclear. Here, we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity. In response to stimulation by inflammatory cytokines, MSCs exhibited a dramatic increase in the consumption of glucose, which was accompanied by an enhanced use of nicotinamide adenine dinucleotide (NAD) and increased expression of nicotinamide phosphoribosyltransferase (NAMPT), a central enzyme in the salvage pathway for NAD production. When NAD synthesis was blocked by inhibiting or depleting NAMPT, the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated. Consequently, when NAD metabolism in MSCs was perturbed, their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury. Further analysis revealed that NAMPT-driven production of NAD was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs. Furthermore, the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle, which led to hypoxia-inducible factor 1α (HIF-1α) stabilization and subsequently increased the transcription of key glycolytic genes, thereby persistently maintaining glycolytic flux. This study demonstrated that unlike its proinflammatory role in immune cells, NAD metabolism governs the anti-inflammatory function of MSCs during inflammation.
间充质干细胞（MSCs）具有强大的免疫调节功能，是治疗炎症性疾病的有前途的治疗方法。这种能力不是先天的，而是由炎症细胞因子激活或“许可”的。许可机制尚不清楚。在这里，我们研究了炎症细胞因子是否通过代谢重编程 MSCs 来赋予这种免疫调节能力。MSCs 对炎症细胞因子的刺激反应表现出葡萄糖消耗的急剧增加，伴随着烟酰胺腺嘌呤二核苷酸（NAD）的增强利用和烟酰胺磷酸核糖转移酶（NAMPT）的表达增加，NAMPT 是 NAD 产生补救途径中的关键酶。当通过抑制或耗尽 NAMPT 阻断 NAD 合成时，炎症细胞因子诱导的 MSCs 的免疫抑制功能大大减弱。因此，当 MSCs 中的 NAD 代谢受到干扰时，患有炎症性肠病和急性肝损伤的小鼠的治疗益处降低。进一步分析表明，NAMPT 驱动的 NAD 产生对于炎症细胞因子诱导的 MSCs 中糖酵解的增加至关重要。此外，糖酵解的增加导致三羧酸循环中琥珀酸的积累，导致缺氧诱导因子 1α（HIF-1α）稳定化，随后增加关键糖酵解基因的转录，从而持续维持糖酵解通量。这项研究表明，与在免疫细胞中的促炎作用不同，NAD 代谢在炎症期间控制 MSCs 的抗炎功能。
