Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 200062 Shanghai, China; Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, 200062 Shanghai, China.
Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
Clin Immunol. 2023 Sep;254:109698. doi: 10.1016/j.clim.2023.109698. Epub 2023 Jul 20.
Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.
糖酵解增强对于脓毒症期间巨噬细胞的促炎反应至关重要。激活转录因子 4（ATF4）在调节肝细胞和脂肪细胞中的葡萄糖和脂质代谢平衡方面发挥着重要作用。然而，其在脓毒症巨噬细胞中的免疫代谢作用在很大程度上尚不清楚。在本研究中，我们发现脓毒症患者外周血单核细胞（PBMC）中 ATF4 的表达增加，并与葡萄糖代谢有关。Atf4 敲低特异性降低了小鼠脂多糖（LPS）诱导的脾巨噬细胞和血清促炎细胞因子水平。此外，Atf4 敲低部分阻断了 LPS 诱导的 RAW264.7 中促炎细胞因子、乳酸积累和糖酵解能力。机制上，ATF4 与己糖激酶 2（HK2）的启动子区域结合，并通过泛素化修饰与低氧诱导因子 1α（HIF-1α）相互作用，从而稳定 HIF-1α，以响应 LPS。此外，ATF4-HIF-1α-HK2-糖酵解轴通过哺乳动物雷帕霉素靶蛋白（mTOR）的激活在巨噬细胞中引发促炎反应。重要的是，Atf4 过表达可改善 LPS 诱导的耐受巨噬细胞中促炎细胞因子、乳酸分泌和 HK2 表达水平的降低。总之，我们提出了 ATF4 的一个新功能，即作为一种关键的糖酵解激活剂，有助于脓毒症中巨噬细胞的促炎反应和免疫耐受。因此，ATF4 可能成为脓毒症免疫治疗的一个潜在新靶点。
