Qu Xiaoye, Xu Dongwei, Yang Tao, Tian Yizhu, King Christopher T, Wang Xiao, Sheng Mingwei, Lin Yuanbang, Bian Xiyun, Li Changyong, Jiang Longfeng, Xia Qiang, Farmer Douglas G, Ke Bibo
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA; Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Redox Biol. 2025 Feb;79:103455. doi: 10.1016/j.redox.2024.103455. Epub 2024 Dec 4.
Dishevelled 2 (Dvl2) is a key mediator of the Wingless/Wnt signaling pathway that regulates cell proliferation, migration, and immune function. However, little is known about the role of macrophage Dvl2 in modulating NOD1-mediated pyroptosis and hepatocyte death in oxidative stress-induced inflammatory liver injury. In a mouse model of oxidative stress-induced liver inflammation, mice with myeloid-specific Dvl2 knockout (Dvl2) displayed exacerbated ischemia/reperfusion (IR) stress-induced hepatocellular damage with increased serum ALT levels, oxidative stress, and proinflammatory mediators. Unlike in Dvl2 controls, Dvl2 enhanced NOD1, caspase-1, GSDMD, and NF-κB activation in liver macrophages after IR. Interestingly, IR stress enhanced YAP colocalized with HSF1 in Dvl2 macrophages, while macrophage Dvl2 deficiency reduced YAP and HSF1 colocalization in the nucleus under inflammatory conditions. Importantly, Dvl2 deletion diminished nuclear YAP interacted with HSF1 and augmented NOD1/caspase-1 and GSDMD activation in response to inflammatory stimulation. However, Dvl2 activation increased YAP interaction with HSF1 and activated HSF1 target gene eEF2, inhibiting NOD1/caspase-1, GSDMD, and NF-κB activity. Moreover, macrophage eEF2 deletion increased the NOD1-caspase-1 interaction, GSDMD activation, HMGB1 release, and hepatocyte LDH release after macrophage/hepatocyte co-culture. Adoptive transfer of eEF2-expressing macrophages in Dvl2 mice alleviated IR-triggered liver inflammation and hepatocellular damage. Therefore, macrophage Dvl2 deficiency promotes NOD1-mediated pyroptosis and exacerbates IR-induced hepatocellular death by disrupting the YAP-HSF1 axis. eEF2 is crucial for modulating NOD1-driven pyroptosis, inflammatory response, and hepatocyte death. Our findings underscore a novel role of macrophage Dvl2 in modulating liver inflammatory injury and imply the therapeutic potential in organ IRI and transplant recipients.
Dishevelled 2（Dvl2）是无翅型/翼状螺旋转录因子（Wingless/Wnt）信号通路的关键介质，该信号通路可调节细胞增殖、迁移和免疫功能。然而，关于巨噬细胞Dvl2在调节NOD1介导的细胞焦亡以及氧化应激诱导的炎症性肝损伤中肝细胞死亡方面的作用，我们所知甚少。在氧化应激诱导的肝脏炎症小鼠模型中，髓系特异性Dvl2基因敲除（Dvl2-/-）小鼠表现出缺血/再灌注（IR）应激诱导的肝细胞损伤加剧，血清谷丙转氨酶（ALT）水平升高、氧化应激和促炎介质增加。与Dvl2对照组不同，IR后Dvl2-/-增强了肝脏巨噬细胞中NOD1、半胱天冬酶-1（caspase-1）、Gasdermin D（GSDMD）和核因子κB（NF-κB）的激活。有趣的是，IR应激增强了Dvl2-/-巨噬细胞中Yes相关蛋白（YAP）与热休克因子1（HSF1）的共定位，而巨噬细胞Dvl2缺陷在炎症条件下减少了细胞核中YAP与HSF1的共定位。重要的是，Dvl2缺失减少了细胞核中YAP与HSF1的相互作用，并增强了炎症刺激后NOD1/caspase-1和GSDMD的激活。然而，Dvl2激活增加了YAP与HSF1的相互作用，并激活了HSF1靶基因真核翻译延伸因子2（eEF2），抑制了NOD1/caspase-1、GSDMD和NF-κB的活性。此外，巨噬细胞eEF2缺失增加了巨噬细胞/肝细胞共培养后NOD1与caspase-1的相互作用、GSDMD激活、高迁移率族蛋白B1（HMGB1）释放和肝细胞乳酸脱氢酶（LDH）释放。在Dvl2-/-小鼠中过继转移表达eEF2的巨噬细胞可减轻IR引发的肝脏炎症和肝细胞损伤。因此，巨噬细胞Dvl2缺陷通过破坏YAP-HSF1轴促进NOD1介导的细胞焦亡并加剧IR诱导的肝细胞死亡。eEF2对于调节NOD1驱动的细胞焦亡、炎症反应和肝细胞死亡至关重要。我们的研究结果强调了巨噬细胞Dvl2在调节肝脏炎症损伤中的新作用，并暗示了其在器官缺血再灌注损伤（IRI）和移植受者中的治疗潜力。
