严重创伤后树突状细胞AhR-IDO1信号轴紊乱及调节策略研究

There are limited countermeasures for the prevention of post-traumatic sepsis. The resistant strategy that aims at killing pathogenic microorganism has led to the rising prevalence of multi-drug-resistant pathogens, so current researches in this field are focusing on how to develop the tolerant strategy that would increase the ability of patients’ own bodies to tolerate infection. Based on the published viewpoint that aryl hydrocarbon receptor (AhR)-indoleamine 2-3 dioxygenase 1 (IDO1) signal axis in dendritic cells (DC) plays an indispensible role in the induction of sepsis tolerance and on our previous study, we propose the hypothesis that the disorder of AhR-IDO1 signal axis in DC following severe trauma occurs, which participates in mediating host susceptibility to post-traumatic sepsis. In this study we will further confirm the alterations of genomic pathway and nongenomic pathway of AhR-IDO1 signal axis in DC of mice following trauma, clarify the roles of these changes in rendering the host susceptible or tolerant to sepsis, identify again AhR ligands reported publically and subgroup them, try to reverse the aberrant DC functions and the susceptibleness to post-traumatic sepsis by both using selected AhR ligands and modulating the levels of key molecules of this signal axis, verify the synergistic effect of combined application of tolerant strategy that we explored here and the resistant strategy such as the use of antibiotics for the prevention and even treatment of post-traumatic sepsis. This study will incredibly shows its clinical significance of developing novel medical interventions through enhancing the resilience of trauma patients to more effectively cope with invading pathogens and sepsis.

严重创伤后预防脓毒症的措施有限，以杀灭病原微生物为目标的“抵抗”策略导致的多重耐药菌感染已构成临床威胁，故以增强机体对感染耐受能力为目标的“耐受”策略正成为研究热点。基于“树突状细胞（DC）的芳香烃受体（AhR）—吲哚胺2,3双加氧酶1（IDO1）信号轴对脓毒症的耐受诱导不可或缺”，结合本团队前期研究结果，我们提出“严重创伤后DC的AhR-IDO1信号轴发生紊乱，并参与介导后续脓毒症发生”的科学假设。本项目拟进一步明确创伤小鼠DC的该信号轴基因组、非基因组通路的变化规律；阐明二者在诱导脓毒症易感/耐受中的作用；重新甄别并选择性应用AhR配体，同时调节该信号轴关键分子水平，试图逆转创伤所致的DC功能失衡以及对脓毒症的易感状态；验证该“耐受”策略与抗生素（“抵抗”策略）联用对创伤后脓毒症防治的协同效应。该研究对发掘通过改变创伤后机体的适应力进而应对感染病原体侵袭的新策略无疑具有重要的临床意义。

严重创伤后预防脓毒症的措施有限，以杀灭病原微生物为目标的“抵抗”策略导致的多重耐药菌感染已构成临床威胁，故以增强机体对感染耐受能力为目标的“耐受”策略正成为研究热点。本项目基于“严重创伤后抗原递呈细胞（包括DC）的AhR驱动的信号轴发生紊乱，并参与介导后续脓毒症发生”的科学假设，开展了如下研究：①证实小鼠活化巨噬细胞、DC的AhR基因组、非基因组通路紊乱，并揭示其在介导创伤后脓毒症中的作用；②发掘针对AhR信号轴的抗细菌感染拮抗措施；③探索严重创伤患者外周血单个核细胞（PBMC）中AhR—CYP1A1—12HETE变化及其与不良预后的关联。重要结果如下：①获得创（烧）伤模型小鼠DC功能改变与相关信号通路紊乱的证据；②发现抗原递呈细胞活化过程中“AhR—Src—Stat3—IL-10”非基因组信号轴可能是一条新型的抗感染“耐受”通路；③发现本实验室证实的新型AhR调节剂－吴茱萸碱对DC的功能具有调节作用，对脓毒症小鼠具有保护效应；④首次证实创伤小鼠脾脏DC免疫功能受抑制的同时，伴随DC的感染“耐受”信号通路异常活化；⑤通过临床转化研究（ChiCTR1800018496；ChiCTR1800018646；ChiCTR1800019845；ChiCTR1800019846），发现AhR—CYP1A1—12HETE信号轴与创伤患者死亡、脓毒症发生密切相关。该项目的科学意义在于提示了AhR—CYP1A1—12HETE信号轴可能在创伤救治领域具有应用前景：①作为生物标志物用于创伤后不良预后的辅助判定；②针对该信号轴的调控药物（如本团队发现的吴茱萸碱、安石榴苷、黄芩素铝胶囊）可能有助于拮抗创伤后感染、脓毒症、多器官功能损害以及死亡的发生。