■原位肝移植术后持续胆汁淤积与预后不良相关。在这项研究中,我们的目的是研究牛磺酸-β-胞嘧啶酸(TβMCA)的积累,由于肝脏缺血/再灌注(IR)应激过程中胆汁酸(BA)代谢的重编程,减轻肝脏炎症。
使用来自鼠肝IR模型的转录组数据进行独创性途径分析。三种不同的肝脏IR模型(肝温IR,胆管分离-IR,采用胆总管结扎术-IR)。我们产生了腺相关病毒转染的小鼠和CD11b-DTR小鼠,以评估BA在调节髓样S1PR2-GSDMD轴中的作用。使用靶向代谢组学分析肝BA水平。最后,通过人肝移植活检的RNA-seq验证了BA代谢重编程与肝脏S1PR2水平之间的相关性.
■我们发现BA代谢在IR应激下在鼠肝细胞中经历了重编程,导致TβMCA合成增加,酶CYP2C70催化。肝脏TβMCA水平与肝脏炎症的严重程度呈负相关。如血清IL-1β水平所示。抑制肝CYP2C70导致TβMCA产生减少,随后增加血清IL-1β水平并加剧IR损伤。此外,我们的研究结果表明,TβMCA能够以髓系特异性S1PR2-GSDMD依赖性方式抑制巨噬细胞的典型炎性体活化并减弱炎症反应.此外,Gly-βMCA,TβMCA的衍生物,能有效减轻体内炎症损伤,抑制体外人巨噬细胞的细胞凋亡。
■IR应力协调肝脏BA代谢以产生TβMCA,通过抑制髓样S1PR2-GSDMD轴来减轻肝脏炎症损伤。胆汁酸在肝再灌注损伤中具有免疫调节功能,可以指导治疗策略。
■我们的研究表明,肝脏缺血再灌注应激触发胆汁酸代谢的重编程。这作为一种适应性机制,通过调节S1PR2-GSDMD轴来减轻炎症损伤,从而控制IL-1β从巨噬细胞的释放。我们的结果强调了胆汁酸在调节肝细胞-免疫细胞串扰中的关键作用,这证明了在肝再灌注损伤中的免疫调节功能,可以指导针对胆汁酸及其受体的治疗策略。
UNASSIGNED: Persistent cholestasis has been associated with poor prognosis after orthotopic liver transplantation. In this study, we aimed to investigate how the accumulation of tauro-beta-muricholic acid (TβMCA), resulting from the reprogramming of bile acid (BA) metabolism during liver ischemia/reperfusion (IR) stress, attenuates liver inflammation.
UNASSIGNED: Ingenuity Pathway Analysis was performed using transcriptome data from a murine hepatic IR model. Three different models of hepatic IR (liver warm IR, bile duct separation-IR, common bile duct ligation-IR) were employed. We generated adeno-associated virus-transfected mice and CD11b-DTR mice to assess the role of BAs in regulating the myeloid S1PR2-
GSDMD axis. Hepatic BA levels were analyzed using targeted metabolomics. Finally, the correlation between the reprogramming of BA metabolism and hepatic S1PR2 levels was validated through RNA-seq of human liver transplant biopsies.
UNASSIGNED: We found that BA metabolism underwent reprogramming in murine hepatocytes under IR stress, leading to increased synthesis of TβMCA, catalyzed by the enzyme CYP2C70. The levels of hepatic TβMCA were negatively correlated with the severity of hepatic inflammation, as indicated by the serum IL-1β levels. Inhibition of hepatic CYP2C70 resulted in reduced TβMCA production, which subsequently increased serum IL-1β levels and exacerbated IR injury. Moreover, our findings suggested that TβMCA could inhibit canonical inflammasome activation in macrophages and attenuate inflammatory responses in a myeloid-specific S1PR2-
GSDMD-dependent manner. Additionally, Gly-βMCA, a derivative of TβMCA, could effectively attenuate inflammatory injury in vivo and inhibit human macrophage pyroptosis in vitro.
UNASSIGNED: IR stress orchestrates hepatic BA metabolism to generate TβMCA, which attenuates hepatic inflammatory injury by inhibiting the myeloid S1PR2-
GSDMD axis. Bile acids have immunomodulatory functions in liver reperfusion injury that may guide therapeutic strategies.
UNASSIGNED: Our research reveals that liver ischemia-reperfusion stress triggers reprogramming of bile acid metabolism. This functions as an adaptive mechanism to mitigate inflammatory injury by regulating the S1PR2-
GSDMD axis, thereby controlling the release of IL-1β from macrophages. Our results highlight the crucial role of bile acids in regulating hepatocyte-immune cell crosstalk, which demonstrates an immunomodulatory function in liver reperfusion injury that may guide therapeutic strategies targeting bile acids and their receptors.