Amer Johnny, Salhab Ahmad, Ariel Amiram, Safadi Rifaat
The Liver Institute, Hadassah Medical Hospital, Jerusalem 91120, Israel.
The Department of Human Biology, University of Haifa, Haifa 3498838, Israel.
Cells. 2025 Jun 20;14(13):941. doi: 10.3390/cells14130941.
The STING (Stimulator of Interferon Genes) pathway plays a vital role in the body's innate immune defense system, primarily involved in DNA sensing and type I interferon production. While STING is well-established in various immune cells, its role in natural killer (NK) cells, particularly within the context of liver fibrosis, remains inadequately explored. The current study investigates the relationship between STING expression, NK cell activity, and insulin receptor (IR) signaling in patients with metabolic dysfunction-associated steatohepatitis (MASH). Peripheral NK cells were isolated from healthy controls and MASH patients with varying stages of liver fibrosis (early: F1/F2; advanced: F3/F4). The expressions of STING, IR, NK cell activation markers (CD107a, NKp46), and NK cell inhibitory markers (LAIR-1, Siglec-7) were assessed using flow cytometry. NK cell cytotoxicity against primary hepatic stellate cells (pHSCs) was evaluated through apoptosis assays. STING agonists (2'3'-cGAMP and DMXAA) were used to stimulate NK cells, and their effects on STING expression, NK cell activation, and cytotoxicity were measured. Additionally, the impact of insulin signaling on STING expression and NK cell function was examined. Our results demonstrate that STING expression in NK cells correlates with disease severity in liver fibrosis. NK cells from MASH patients with advanced fibrosis (F3/F4) showed inhibited STING protein levels that were statistically comparable to healthy NK cells and accompanied by impaired cytotoxicity and decreased IFN-γ production. In contrast, NK cells from early fibrosis (F1/F2) exhibited higher STING expression and better functional activity. STING agonist treatment (2'3'-cGAMP) restored STING expression and enhanced NK cell activity across all fibrosis stages. Furthermore, insulin treatment and combined insulin and 2'3'-cGAMP treatment synergistically upregulated both IR and STING expressions, leading to improved NK cell function and increased cytotoxicity, particularly in advanced fibrosis. Our results highlight the potential of targeting STING and insulin signaling pathways as a therapeutic approach in restoring NK cell function and enhance immune surveillance in liver fibrosis.
干扰素基因刺激蛋白（STING）通路在机体的固有免疫防御系统中发挥着至关重要的作用，主要参与DNA感知和I型干扰素的产生。虽然STING在各种免疫细胞中已得到充分证实，但其在自然杀伤（NK）细胞中的作用，尤其是在肝纤维化背景下，仍未得到充分探索。本研究调查了代谢功能障碍相关脂肪性肝炎（MASH）患者中STING表达、NK细胞活性与胰岛素受体（IR）信号传导之间的关系。从健康对照和不同肝纤维化阶段（早期：F1/F2；晚期：F3/F4）的MASH患者中分离外周血NK细胞。使用流式细胞术评估STING、IR、NK细胞活化标志物（CD107a、NKp46）和NK细胞抑制标志物（LAIR-1、Siglec-7）的表达。通过凋亡检测评估NK细胞对原代肝星状细胞（pHSC）的细胞毒性。使用STING激动剂（2'3'-cGAMP和DMXAA）刺激NK细胞，并测量它们对STING表达、NK细胞活化和细胞毒性的影响。此外，还研究了胰岛素信号传导对STING表达和NK细胞功能的影响。我们的结果表明，NK细胞中的STING表达与肝纤维化的疾病严重程度相关。晚期纤维化（F3/F4）的MASH患者的NK细胞显示STING蛋白水平受到抑制，在统计学上与健康NK细胞相当，同时伴有细胞毒性受损和IFN-γ产生减少。相比之下，早期纤维化（F1/F2）的NK细胞表现出更高的STING表达和更好的功能活性。STING激动剂治疗（2'3'-cGAMP）恢复了STING表达，并增强了所有纤维化阶段的NK细胞活性。此外，胰岛素治疗以及胰岛素与2'3'-cGAMP联合治疗协同上调了IR和STING的表达，从而改善了NK细胞功能并增加了细胞毒性，尤其是在晚期纤维化中。我们的结果凸显了靶向STING和胰岛素信号通路作为恢复NK细胞功能和增强肝纤维化免疫监视的治疗方法的潜力。
