PDF(Pubmed)
Abstract：
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.
摘要：
结节性硬化症1（TSC1）在调节先天免疫中起重要作用。然而,TSC1在调节肝脏缺血/再灌注损伤(I/R)的氧化应激反应和肝脏炎症中的确切作用尚不清楚.在小鼠肝脏I/R损伤模型中,髓系特异性TSC1缺失抑制AKT和MST1磷酸化，并减少NRF2的积累，而激活的TLR4/NF-κB通路，导致肝脏炎症增加。过表达AKT或MST1的巨噬细胞的过继转移，在骨髓特异性TSC1敲除小鼠中,或Keap1破坏促进NRF2激活,但降低TLR4活性并减轻I/R诱导的肝脏炎症。机械上,TSC1在巨噬细胞中促进AKT和MST1磷酸化，并保护NRF2免受Keap1介导的泛素化。此外，在TSC1敲除的巨噬细胞中过表达AKT或MST1上调NRF2表达，下调TLR4/NF-κB，导致炎症因子减少，ROS和炎症细胞因子介导的肝细胞凋亡。引人注目的是，NRF2缺陷型巨噬细胞中的TSC1诱导未能逆转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介导的泛素化增加NRF2水平，并调节肝脏I/R损伤中氧化应激驱动的炎症反应。我们的发现强调了巨噬细胞TSC1作为先天免疫的新型调节因子的关键作用，并暗示了移植受体中无菌肝脏炎症治疗的治疗潜力。巨噬细胞TSC1介导的AKT/MST1/NRF2信号通路在I/R触发的肝脏炎症中的示意图。巨噬细胞TSC1可以在I/R应激的肝脏中被激活。TSC1激活促进AKT和MST1的磷酸化，进而增加NRF2表达并抑制ROS产生和TLR4/NF-κB激活，导致I/R触发的肝损伤中肝细胞凋亡减少。
