Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
Department of emergency, The PLA Rocket Force Characteristic Medical Center, Beijing, 100085, China.
Int Immunopharmacol. 2022 Aug;109:108809. doi: 10.1016/j.intimp.2022.108809. Epub 2022 Apr 30.
Regulated cell death profoundly affects on the progress of inflammatory and immune responses in various acute inflammatory diseases, as seen in sepsis and trauma. However, the mechanisms underlying CD4 T cells death have not yet been fully addressed. We demonstrated that interferon genes (STING) promoted excessive Poly (ADP-ribose) polymerase 1 (PARP-1) activity stimulated by endotoxin, which in turn induced apoptosis-inducing factor (AIF)-independent but PARP-1 dependent programmed cell death. Elevated PARP-1 activity triggered a cascade of molecular events, including PAR polymer release from the nucleus and the nicotinamide adenine dinucleotide (NAD) and ATP depletion. Interestingly, translocation of AIF, a biochemical signature for PARP-1-dependent parthanatos, was not observed in the present study, suggesting a non-canonical mechanism of CD4 T cells parthanatos. In this study, we also identify a STING-mediated mechanism of necrotic cell death in CD4 T cells in septic animals. Furthermore, we revealed wider effects of STING on the mortality in mice when PARP-1 gene inhibited. These findings reveal that STING signaling and targeting PARP-1/PAR pathway in CD4 T cells may present a new therapeutic strategy for the treatment of acute systemic inflammatory diseases.
程序性细胞死亡深刻地影响着各种急性炎症性疾病中炎症和免疫反应的进展，如脓毒症和创伤。然而，CD4 T 细胞死亡的机制尚未完全阐明。我们发现干扰素基因（STING）促进了内毒素刺激下的聚（ADP-核糖）聚合酶 1（PARP-1）过度激活，进而诱导了凋亡诱导因子（AIF）非依赖性但依赖 PARP-1 的程序性细胞死亡。升高的 PARP-1 活性引发了一系列分子事件，包括 PAR 聚合物从核内释放以及烟酰胺腺嘌呤二核苷酸（NAD）和三磷酸腺苷（ATP）的耗竭。有趣的是，在本研究中未观察到 AIF 的易位，AIF 是 PARP-1 依赖性细胞坏死的生化特征，这表明 CD4 T 细胞坏死存在非经典机制。在这项研究中，我们还在脓毒症动物的 CD4 T 细胞中发现了一种 STING 介导的坏死细胞死亡机制。此外，当 PARP-1 基因被抑制时，我们揭示了 STING 对小鼠死亡率的更广泛影响。这些发现表明，STING 信号通路和靶向 CD4 T 细胞中的 PARP-1/PAR 通路可能为治疗急性全身性炎症性疾病提供新的治疗策略。
