脓毒症时巨噬细胞CYP1A1过度活化导致宿主感染耐受能力降低的分子机制

Macrophages play an important role in the pathophysiology of sepsis. Based on the published viewpoint that aryl hydrocarbon receptor (AhR) in macrophages participates in the modulation for sepsis tolerance and on our previous findings that the loss of AhR gene can not stop the activation of its downstream molecule—cytochrome P450, family 1, member A1 (CYPlAl), which exerts negative modulatory effect on host infection tolerance capability, we propose the hypothesis that the over-activation of CYPlAl induced by its turbulenced signal axis following sepsis may decrease the host infection tolerance capability. In this study we will further reveal which non-AhR-dependent pathway may also modulate CYPlAl transcription in macrophages from septic mice, clarify the changes and roles of its downstream signal pathway CYP1A1—12-HETE—JNK—AP-1 in modulating infection tolerance, identify again and selectively use CYPlAl modulators and interfere with the levels of key molecules of this signal axis to strengthen host infection tolerance, verify the synergistic effect of combined application of tolerant strategy and resistant strategy for the prevention and even treatment of sepsis. This study will not only help to elucidate the role and status of macrophages’ CYPlAl in host response against infection, but also establish the foundation for finding novel intervention targets and developing novel therapeutic strategies for sepsis.

巨噬细胞(Mø)在脓毒症病理进程中扮演重要角色。既然“Mø的芳香烃受体(AhR)参与机体对脓毒症的耐受调节”，结合我们发现“Mø的AhR基因缺失不能阻止其下游分子—细胞色素酶 P450家族成员lAl(CYPlAl)的表达，且后者对机体感染耐受能力具有负性调控作用”的事实，我们提出“脓毒症时Mø中CYPlAl信号通路紊乱致其过度活化进而降低宿主的感染耐受能力”的科学假设。本项目拟弄清脓毒症小鼠Mø的CYPlAl转录还可受何种AhR非依赖信号通路的调控；揭示其下游信号轴CYP1A1—12-HETE—JNK—AP-1对感染耐受的调节作用；重新甄别并选择性应用CYP1A1调节剂，同时干预其上下游关键分子以提升宿主感染耐受能力；确证联合应用“耐受”、“抵抗”策略对脓毒症防治的协同效应。这不仅有助于揭示Mø的CYP1A1在抗感染应答中的作用与地位，而且可为探寻脓毒症干预新靶点及发掘治疗新措施奠定基础。

巨噬细胞在脓毒症病理进程中扮演重要角色, 我们提出“脓毒症时巨噬细胞中CYPlAl信号通路紊乱致其过度活化进而降低宿主的感染耐受能力”的科学假设，进而研究了脓毒症小鼠巨噬细胞的CYPlAl转录还可受何种AhR非依赖信号通路的调控；揭示其下游信号轴CYP1A1—12-HETE—JNK—AP-1对感染耐受的调节作用；重新甄别并选择性应用CYP1A1调节剂，同时干预其上下游关键分子以提升宿主感染耐受能力；确证联合应用“耐受”、“抵抗”策略对脓毒症防治的协同效应。主要结果如下：首次发现脓毒症时CYP1A1可强化巨噬细胞炎症反应并抑制其对细菌的吞噬作用；CYP1A1增加精氨酸酶-1表达并通过靶向 JAK1/STAT6抑制LPS诱导的小鼠腹膜炎；发现CYP1A1抑制剂玫瑰树碱可抑制JNK/AP-1通路以减轻LPS诱导的巨噬细胞活化反应；首次证实了“宿主CYP1A1-微生物代谢轴”介导MRSA腹腔脓毒症小鼠肠屏障损伤。该研究不仅有助于揭示巨噬细胞的CYP1A1在抗感染应答中的作用与地位，而且可为探寻脓毒症干预新靶点及发掘治疗新措施奠定基础。