Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
J Hepatol. 2022 Apr;76(4):896-909. doi: 10.1016/j.jhep.2021.11.026. Epub 2021 Dec 3.
BACKGROUND & AIMS: Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses remains unclear. Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. Whether SIRT1 signaling is essential in myeloid cell activation remains uncertain, while the molecular communication between Ikaros and SIRT1, two major transcriptional regulators, has not been studied.
We undertook molecular and functional studies to interrogate the significance of the myeloid Ikaros-SIRT1 axis in innate immune activation and whether it may serve as a homeostatic sentinel in human liver transplant recipients (hepatic biopsies) and murine models of sterile hepatic inflammation (liver warm ischemia-reperfusion injury in wild-type, myeloid-specific Sirt1-knockout, and CD11b-DTR mice) as well as primary bone marrow-derived macrophage (BMM) cultures (Ikaros silencing vs. overexpression).
In our clinical study, we identified increased post-reperfusion hepatic Ikaros levels, accompanied by augmented inflammasome signaling yet depressed SIRT1, as a mechanism of hepatocellular damage in liver transplant recipients. In our experimental studies, we identified infiltrating macrophages as the major source of Ikaros in IR-stressed mouse livers. Then, we demonstrated that Ikaros-regulated pyroptosis - induced by canonical inflammasome signaling in BMM cultures - was SIRT1 dependent. Consistent with the latter, myeloid-specific Ikaros signaling augmented hepatic pyroptosis to aggravate pro-inflammatory responses in vivo by negatively regulating SIRT1 in an AMPK-dependent manner. Finally, myeloid-specific SIRT1 was required to suppress pyroptosis, pro-inflammatory phenotype, and ultimately mitigate hepatocellular injury in ischemia-stressed murine livers.
These findings identify the Ikaros-SIRT1 axis as a novel mechanistic biomarker of pyroptosis and a putative checkpoint regulator of homeostasis in response to acute hepatic stress/injury in mouse and human livers.
This report describes how crosstalk between Ikaros and SIRT1, two major transcriptional regulators, influence acute hepatic inflammation in murine models of liver ischemia-reperfusion injury and liver transplant recipients. We show that the myeloid Ikaros-SIRT1 axis regulates inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. Thus, the Ikaros-SIRT1 axis may serve as a novel checkpoint regulator that is required for homeostasis in response to acute liver injury in mice and humans.
尽管 Ikaros（IKZF1）是白细胞淋巴生成和分化中一种成熟的转录调节因子，但它在髓系固有免疫反应中的作用仍不清楚。Sirtuin 1（SIRT1）是一种参与细胞衰老、炎症和应激抵抗的组蛋白/蛋白去乙酰化酶。SIRT1 信号是否对髓系细胞激活至关重要尚不确定，而 Ikaros 和 SIRT1 这两个主要转录调节因子之间的分子通信尚未得到研究。
我们进行了分子和功能研究，以探究髓系 Ikaros-SIRT1 轴在固有免疫激活中的意义，以及它是否可以作为人类肝移植受者（肝活检）和无菌性肝炎症模型（野生型、髓系特异性 Sirt1 敲除和 CD11b-DTR 小鼠的肝脏热缺血再灌注损伤）以及原代骨髓来源的巨噬细胞（BMM）培养物（Ikaros 沉默与过表达）中的稳态监测器。
在我们的临床研究中，我们发现再灌注后肝组织中 Ikaros 水平升高，同时炎症小体信号增强而 SIRT1 水平降低，这是肝移植受者肝细胞损伤的一种机制。在我们的实验研究中，我们发现浸润的巨噬细胞是 IR 应激小鼠肝脏中 Ikaros 的主要来源。然后，我们证明了 Ikaros 调节的细胞焦亡 - 在 BMM 培养物中通过经典炎症小体信号诱导 - 依赖于 SIRT1。与后者一致的是，髓系特异性 Ikaros 信号通过 AMPK 依赖性方式负调节 SIRT1，从而增强肝脏细胞焦亡，加剧体内促炎反应。最后，髓系特异性 SIRT1 是抑制细胞焦亡、促炎表型和减轻缺血应激小鼠肝脏肝细胞损伤所必需的。
这些发现确定了 Ikaros-SIRT1 轴作为细胞焦亡的新型机制生物标志物，并作为小鼠和人类肝脏急性应激/损伤时体内平衡的潜在检查点调节剂。
本报告描述了转录调节因子 Ikaros 和 SIRT1 之间的串扰如何影响肝缺血再灌注损伤的小鼠模型和肝移植受者的急性肝炎症。我们表明，髓系 Ikaros-SIRT1 轴调节应激肝脏中的炎症小体-细胞焦亡和肝细胞损伤。因此，Ikaros-SIRT1 轴可能作为一种新的检查点调节剂，在应对小鼠和人类急性肝损伤时对体内平衡至关重要。
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