Myeloid Ikaros-SIRT1 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed mouse and human liver.
Myeloid Ikaros-SIRT1 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed mouse and human liver.
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DOI：
10.1016/j.jhep.2021.11.026
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发表时间：
2022-04
影响因子：
25.7
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Kadono, Kentaro;Kageyama, Shoichi;Nakamura, Kojiro;Hirao, Hirofumi;Ito, Takahiro;Kojima, Hidenobu;Dery, Kenneth J.;Li, Xiaoling;Kupiec-Weglinski, Jerzy W.
尽管伊卡洛斯（IKZF1）在白细胞淋巴细胞生成和分化中是一种已明确的转录调节因子，但其在髓系固有免疫应答中的作用仍不清楚。沉默调节蛋白1（SIRT1）是一种参与细胞衰老、炎症和抗应激的组蛋白/蛋白质去乙酰化酶。SIRT1信号在髓系细胞激活中是否至关重要仍不确定，而伊卡洛斯和SIRT1这两种主要转录调节因子之间的分子通讯尚未得到研究。
我们进行了分子和功能研究，以探究髓系伊卡洛斯 - SIRT1轴在固有免疫激活中的重要性，以及它是否可作为人类肝移植受者（肝活检）和无菌性肝脏炎症小鼠模型（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）以及原代骨髓来源巨噬细胞（BMM）培养物（伊卡洛斯沉默与过表达）中的内稳态监测因子。
在我们的临床研究中，我们发现再灌注后肝脏伊卡洛斯水平升高，同时伴有炎症小体信号增强但SIRT1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，我们确定浸润的巨噬细胞是缺血再灌注应激小鼠肝脏中伊卡洛斯的主要来源。然后，我们证明了在BMM培养物中由经典炎症小体信号诱导的伊卡洛斯调节的细胞焦亡是依赖于SIRT1的。与后者一致，髓系特异性伊卡洛斯信号通过以AMPK依赖的方式负调节SIRT1，增强肝脏细胞焦亡，从而在体内加重促炎反应。最后，髓系特异性SIRT1是抑制细胞焦亡、促炎表型以及最终减轻缺血应激小鼠肝脏肝细胞损伤所必需的。
这些发现将伊卡洛斯 - SIRT1轴确定为细胞焦亡的一种新型机制生物标志物，以及小鼠和人类肝脏对急性肝脏应激/损伤作出反应时内稳态的一种假定检查点调节因子。
本报告描述了伊卡洛斯和SIRT1这两种主要转录调节因子之间的相互作用如何影响肝脏缺血 - 再灌注损伤小鼠模型和肝移植受者中的急性肝脏炎症。我们表明髓系伊卡洛斯 - 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，伊卡洛斯 - SIRT1轴可能作为一种新型检查点调节因子，对小鼠和人类急性肝损伤时的内稳态是必需的。
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.
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影响因子：
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作者：
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Trebicka J