Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia–reperfusion injury

Author:

Li Jichang,Zhao Jie,Xu Min,Li Meng,Wang Bingrui,Qu Xiaoye,Yu Chang,Hang Hualian,Xia Qiang,Wu Hailong,Sun Xuehua,Gu Jinyang,Kong Xiaoni

Abstract

AbstractPyroptosis, a proinflammatory form of programmed cell death, plays important roles in the pathogenesis of many diseases. Inflammasome activation, which has been shown in hepatic ischemia–reperfusion injury (IRI), is demonstrated to be closely associated with pyroptosis, indicating that pyroptosis may occur and perform functions in hepatic IRI. However, there is no direct evidence showing the function of pyroptosis in hepatic IRI. In this study, by detecting the pyroptosis markers, we showed that pyroptosis may be induced during hepatic IRI. Furthermore, by adopting caspase-1 inhibitors, we showed that inhibition of pyroptosis could significantly ameliorate liver injury and suppress inflammatory response during hepatic IRI. Interestingly, caspase-1 inhibitors have no protective effects on in vitro hepatocytes under hypoxic reoxygenation condition. To investigate pyroptosis induced in which specific cell types may affect hepatic IRI, we generated hepatocyte-specific Gsdmd-knockout (Hep-Gsdmd−/−) and myeloid-specific Gsdmd-knockout (LysmCre+Gsdmdf/f) mice. Functional experiments showed that compared to control mice (Gsdmdf/f), there were alleviated liver injury and inflammation in LysmCre+Gsdmdf/f mice, but not in AlbCre+Gsdmdf/f mice. In parallel in vitro studies, cytokine expression and production decreased in bone-marrow-derived macrophages and Kupffer cells from LysmCre+Gsdmdf/f mice compared to their controls. Our findings demonstrated that pyroptosis in innate immune cells aggravates hepatic IRI and implied that hepatic IRI could be protected by blocking pyroptosis, which may become a potential therapeutic target in the clinic.

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

Reference51 articles.

1. Abe, Y., Hines, I., Zibari, G. & Grisham, M. B. Hepatocellular protection by nitric oxide or nitrite in ischemia and reperfusion injury. Arch. Biochem. Biophys. 484, 232–237 (2009).

2. Nakamura, K. et al. Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J. Hepatol. 67, 1232–1242 (2017).

3. Ma, Z. et al. Melatonin and mitochondrial function during ischemia/reperfusion injury. Cell. Mol. Life Sci. 74, 3989–3998 (2017).

4. Zhai, Y., Petrowsky, H., Hong, J. C., Busuttil, R. W., Kupiec-Weglinski, J. Ischaemia–reperfusion injury in liver transplantation—from bench to bedside. Nat. Rev. Gastroenterol. Hepatol. 10, 79–89 (2013).

5. Guicciardi, M. E., Malhi, H., Mott, J. L. & Gores, G. J. Apoptosis and necrosis in the liver. Compr Physiol 3, 977–1010 (2013).

Cited by 76 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3