Zhang Lina, Cagle Cortney, Nguyen Du Hanh, Gomes Graziela Scheuer, Gromova Barbora, Csizmadia Eva, Karimitar Arian, Lee Ghee Rye, Chen Guanqing, Kokkotou Efi, Grossberg Laurie, Jiang Sizun, Cheifetz Adam S, Kota Satya K, Longhi Maria Serena
Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
School of Medicine, Tufts University, Boston, MA, USA.
Cell Mol Immunol. 2025 May 26. doi: 10.1038/s41423-025-01295-6.
Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease (IBD). CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine, an immune metabolite that is key to tissue homeostasis. Human CD39 is regulated by an endogenous antisense RNA (CD39-AS) that is markedly elevated in IBD Tregs and Th17 cells. In this study, we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients. We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells. Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD. In Th17 cells, silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health. These metabolic effects are also noted in a model of experimental colitis in humanized mice, along with reduced disease activity. Thus, in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity, decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes. Mechanistically, activation of HIF-1α and STAT3 results in the upregulation of CD39-AS in IBD cells. In conclusion, CD39-AS is an important modulator of Treg and Th17 cell metabolism. Interference with this antisense RNA, or the factors favoring its upregulation, might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.
CD39水平缺陷导致炎症性肠病（IBD）中调节性T细胞（Tregs）和辅助性T细胞17（Th17）效应细胞之间的失衡。CD39启动一个ATP水解级联反应，最终生成腺苷，这是一种对组织稳态至关重要的免疫代谢物。人CD39受一种内源性反义RNA（CD39-AS）调控，该反义RNA在IBD的Tregs和Th17细胞中显著升高。在本研究中，我们调查了CD39-AS如何影响健康受试者和IBD患者中Tregs和Th17细胞的功能。我们报告CD39-AS RNA以两种主要剪接变体形式存在，分别由Tregs或Th17细胞特异性表达。通过靶向Tregs中表达的剪接变体的自递送寡核苷酸阻断CD39-AS，会导致葡萄糖转运和糖酵解减少，并增强IBD中Treg的功能和稳定性。在Th17细胞中，CD39-AS的沉默限制氧化反应并改善线粒体健康。在人源化小鼠的实验性结肠炎模型中也观察到了这些代谢效应，同时疾病活动度降低。因此，体内给予靶向Treg或Th17细胞CD39-AS变体的寡核苷酸可限制疾病活动度，降低葡萄糖转运蛋白1（GLUT1）的表达，并改善肠道来源的CD4淋巴细胞中的线粒体健康。从机制上讲，缺氧诱导因子-1α（HIF-1α）和信号转导及转录激活因子3（STAT3）的激活导致IBD细胞中CD39-AS上调。总之，CD39-AS是Treg和Th17细胞代谢的重要调节因子。干扰这种反义RNA或促进其上调的因素，可能通过恢复免疫代谢和Treg功能稳定性来控制IBD中的炎症并阻止疾病进展。
