BCL6 Alleviates Hepatic Ischemia/Reperfusion Injury Via Recruiting SIRT1 to Repress the NF-κB/NLRP3 Pathway.

IF 5.3 2区医学 Q1 IMMUNOLOGY

Transplantation Pub Date : 2025-01-13 DOI:10.1097/TP.0000000000005305

Yulei Gu, Yue Li, Chao Zhang, Yi Liu, Huiting Shi, Xiaoxu Tian, Jiaqi Du, Hao Zhang, Shengli Cao, Lu Gao, Yanzhou Zhang, Guojun Zhao

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引用次数: 0

Abstract

Background: Hepatic ischemia/reperfusion (I/R) injury (HIRI) is an intrinsic phenomenon observed in the process of various liver surgeries. Unfortunately, there are currently few options available to prevent HIRI. Accordingly, we aim to explore the role and key downstream effects of B-cell lymphoma 6 (BCL6) in hepatic I/R (HIR).

Methods: BCL6 expression levels were measured in I/R liver tissue and primary hepatocytes stimulated by hypoxia/reoxygenation (H/R). Moreover, we ascertained the BCL6 effect on HIR in vivo using liver-specific BCL6 knockout mice and adenovirus-BCL6-infected mice. RNA-sequencing, luciferase, chromatin immunoprecipitation, and interactome analysis were combined to identify the direct target and corresponding molecular events contributing to BCL6 function. DNA pull-down was applied to identify upstream of BCL6 in the H/R challenge.

Results: HIR represses BCL6 expression in vivo and in vitro. Hepatic BCL6 overexpression attenuates inflammation and apoptosis after I/R injury, whereas BCL6 deficiency aggravates I/R-induced liver injury. RNA-sequencing showed that BCL6 modulated nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 inflammasome signaling in HIRI. Mechanistically, BCL6 deacetylated nuclear factor kappa-B p65 lysine 310 by recruiting sirtuin 1 (SIRT1), thereby inhibiting the nuclear factor kappa-B/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 pathway. Moreover, overexpression of SIRT1 blocked the detrimental effects of BCL6 depletion. Moreover, EX 527, a SIRT1 inhibitor, vanished protection from BCL6 overexpression. Furthermore, transcription factor 7 was found to mediate the transcription regulation of BCL6 on H/R challenge.

Conclusions: Our results provide the first evidence supporting BCL6 as an important protective agent of HIR. This suggests a potential therapeutic approach for HIR.

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BCL6通过募集SIRT1抑制NF-κB/NLRP3通路减轻肝脏缺血/再灌注损伤

背景：肝缺血/再灌注损伤（HIRI）是各种肝脏手术过程中观察到的固有现象。不幸的是，目前预防HIRI的选择很少。因此，我们的目的是探讨b细胞淋巴瘤6 （BCL6）在肝脏I/R （HIR）中的作用和关键的下游作用。方法：在缺氧/再氧化（H/R）刺激的I/R肝组织和原代肝细胞中检测BCL6的表达水平。此外，我们利用肝脏特异性BCL6敲除小鼠和腺病毒-BCL6感染小鼠在体内确定了BCL6对HIR的影响。rna测序、荧光素酶、染色质免疫沉淀和相互作用组分析相结合，确定了BCL6功能的直接靶点和相应的分子事件。采用DNA下拉法鉴定H/R挑战中BCL6的上游。结果：HIR在体内和体外均抑制BCL6的表达。肝脏BCL6过表达可减轻I/R损伤后的炎症和细胞凋亡，而BCL6缺乏可加重I/R诱导的肝损伤。rna测序结果显示，BCL6调节HIRI中核苷酸结合寡聚化结构域、富亮氨酸重复序列和含pyrin结构域的3个炎性小体信号。机制上，BCL6通过募集sirtuin 1 （SIRT1）使核因子kappa-B p65赖氨酸310去乙酰化，从而抑制核因子kappa-B/核苷酸结合寡聚结构域、富亮氨酸重复序列和含pyrin结构域3通路。此外，SIRT1的过表达阻断了BCL6缺失的有害影响。此外，SIRT1抑制剂ex527对BCL6过表达的保护作用消失。此外，转录因子7介导了BCL6在H/R胁迫下的转录调控。结论：我们的研究结果首次证明BCL6是HIR的重要保护剂。这提示了一种潜在的HIR治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Transplantation 医学-免疫学

CiteScore

8.50

自引率

11.30%

发文量

1906

审稿时长

1 months

期刊介绍： The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year. Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal. Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed. The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.