Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Children's Hospital of Nanjing Medical University, Nanjing, China.
Cell Death Dis. 2024 Feb 15;15(2):146. doi: 10.1038/s41419-024-06538-4.
Tuberous sclerosis complex 1 (TSC1) plays important roles in regulating innate immunity. However, the precise role of TSC1 in macrophages in the regulation of oxidative stress response and hepatic inflammation in liver ischemia/reperfusion injury (I/R) remains unknown. In a mouse model of liver I/R injury, deletion of myeloid-specific TSC1 inhibited AKT and MST1 phosphorylation, and decreased NRF2 accumulation, whereas activated TLR4/NF-κB pathway, leading to increased hepatic inflammation. Adoptive transfer of AKT- or MST1-overexpressing macrophages, or Keap1 disruption in myeloid-specific TSC1-knockout mice promoted NRF2 activation but reduced TLR4 activity and mitigated I/R-induced liver inflammation. Mechanistically, TSC1 in macrophages promoted AKT and MST1 phosphorylation, and protected NRF2 from Keap1-mediated ubiquitination. Furthermore, overexpression AKT or MST1 in TSC1-knockout macrophages upregulated NRF2 expression, downregulated TLR4/NF-κB, resulting in reduced inflammatory factors, ROS and inflammatory cytokine-mediated hepatocyte apoptosis. Strikingly, TSC1 induction in NRF2-deficient macrophages failed to reverse the TLR4/NF-κB activity and production of pro-inflammatory factors. Conclusions: Macrophage TSC1 promoted the activation of the AKT/MST1 signaling pathway, increased NRF2 levels via reducing Keap1-mediated ubiquitination, and modulated oxidative stress-driven inflammatory responses in liver I/R injury. Our findings underscore the critical role of macrophage TSC1 as a novel regulator of innate immunity and imply the therapeutic potential for the treatment of sterile liver inflammation in transplant recipients. Schematic illustration of macrophage TSC1-mediated AKT/MST1/NRF2 signaling pathway in I/R-triggered liver inflammation. Macrophage TSC1 can be activated in I/R-stressed livers. TSC1 activation promotes phosphorylation of AKT and MST1, which in turn increases NRF2 expression and inhibits ROS production and TLR4/NF-κB activation, resulting in reduced hepatocellular apoptosis in I/R-triggered liver injury.
结节性硬化症复合物 1 (TSC1) 在调节先天免疫中发挥重要作用。然而，TSC1 在调节缺血/再灌注损伤 (I/R) 中肝巨噬细胞氧化应激反应和肝炎症的确切作用尚不清楚。在小鼠肝 I/R 损伤模型中，髓系特异性 TSC1 的缺失抑制了 AKT 和 MST1 的磷酸化，并减少了 NRF2 的积累，而激活的 TLR4/NF-κB 途径则导致肝炎症增加。过表达 AKT 或 MST1 的巨噬细胞的过继转移，或髓系特异性 TSC1 敲除小鼠中的 Keap1 破坏，促进了 NRF2 的激活，但降低了 TLR4 的活性，并减轻了 I/R 诱导的肝炎症。在机制上，巨噬细胞中的 TSC1 促进了 AKT 和 MST1 的磷酸化，并保护 NRF2 免受 Keap1 介导的泛素化。此外，在 TSC1 敲除巨噬细胞中过表达 AKT 或 MST1 上调了 NRF2 的表达，下调了 TLR4/NF-κB，从而减少了炎症因子、ROS 和炎症细胞因子介导的肝细胞凋亡。引人注目的是，在 NRF2 缺陷型巨噬细胞中诱导 TSC1 未能逆转 TLR4/NF-κB 活性和促炎因子的产生。结论：巨噬细胞 TSC1 促进 AKT/MST1 信号通路的激活，通过减少 Keap1 介导的泛素化来增加 NRF2 水平，并调节 I/R 损伤中氧化应激驱动的炎症反应。我们的研究结果强调了巨噬细胞 TSC1 作为先天免疫新调节剂的关键作用，并暗示了其在治疗移植受者无菌性肝炎症中的治疗潜力。示意图说明了 I/R 触发的肝炎症中巨噬细胞 TSC1 介导的 AKT/MST1/NRF2 信号通路。在 I/R 应激的肝脏中可以激活巨噬细胞 TSC1。TSC1 的激活促进 AKT 和 MST1 的磷酸化，进而增加 NRF2 的表达并抑制 ROS 的产生和 TLR4/NF-κB 的激活，从而减少 I/R 触发的肝损伤中肝细胞凋亡。
