University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Clinical Surgery, University of Edinburgh, Edinburgh, UK.
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
Cell Rep. 2023 Aug 29;42(8):112763. doi: 10.1016/j.celrep.2023.112763. Epub 2023 Jul 19.
Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1β to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.
犬尿氨酸单加氧酶（KMO）阻断可预防急性胰腺炎（AP）引起的多器官衰竭，但 KMO 与全身炎症之间的联系直到现在才被发现。在这里，我们表明，KMO 产物 3-羟基犬尿氨酸使先天免疫信号在实验性 AP 期间加剧全身炎症。我们发现 KMO 在组织中具有特异性作用，其中仅在肝细胞中缺乏 Kmo 的小鼠具有升高的血浆 3-羟基犬尿氨酸水平，从而引发炎症基因转录。3-羟基犬尿氨酸与白细胞介素-1β协同作用引起细胞凋亡。至关重要的是，血液中 3-羟基犬尿氨酸升高的小鼠更早、更容易死于实验性 AP。在治疗上，用高度选择性的 KMO 抑制剂 GSK898 阻断可挽救表型，降低 3-羟基犬尿氨酸并预防严重疾病和死亡。总之，我们的研究结果确立了 KMO 和 3-羟基犬尿氨酸作为炎症和对无菌炎症的先天免疫反应的调节剂。在危重病期间，全身 KMO 阻断可挽救多器官衰竭引起的过高发病率和死亡率。
