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Hepatic macrophages in liver homeostasis and diseasesdiversity,plasticity and therapeutic opportunities

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Cellular & Molecular Immunology 2021年第1期18卷 45-56页

作者： Yankai Wen Joeri Lambrecht cynthia ju Frank Tacke Department of Anesthesiology McGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTXUSA Department of Hepatology and Gastroenterology Charity University Medicine BerlinBerlinGermany

Macrophages,which are key cellular components of the liver,have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver *** liver injury,resident Kupffer cells(KCs)sense disturbances in homeostasis,interact with hepatic cell populations and release chemokines to recruit circulating leukocytes,including monocytes,which subsequently differentiate into monocyte-derived macrophages(MoMφs)in the *** KCs and MoMφs contribute to both the progression and resolution of tissue inflammation and injury in various liver *** diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver *** this review,we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

关键词： Kupffer cells monocyte-derived macrophages liver inflammation liver fibrosis liver cancer

Hepatic macrophages in drug-induced liver injury

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Liver Research 2019年第3期3卷 170-175页

作者： Zhao Shan cynthia ju Center for Life Sciences School of Life SciencesYunnan UniversityKunmingChina Department of Anesthesiology UTHealth McGovern Medical SchoolHoustonTXUSA

Drug-induced liver injury(DILI)is a major public health *** DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United ***,the most problematic type of DILI affecting drug development and health care is idiosyncratic DILI,which occurs unpredictably in a small population of patients taking the drug and the latency could be several weeks to *** knowledge on the pathogenesis of DILI suggest that hepatic macrophages play a central role in the initiation,progression and restoration stages of DILI,which make hepatic macrophages attractive as therapeutic *** macrophages consist of liver resident macrophages(also known as Kupffer cells,KCs)and infiltrating monocyte-derived macrophages(MoMF).There is a growing appreciation that hepatic macrophage is very plastic,and assumes diverse phenotypes and functions in response to micro-environmental *** this review,we will summarize studies on the role of hepatic macrophages in both intrinsic DILI and idiosyncratic DILI,followed by discussing the prognostic and therapeutic potentials of targeting hepatic macrophages and the obstacles in studying hepatic macrophages.

关键词： Hepatic macrophages Acetaminophen(APAP) Drug Liver injury Intrinsic drug-induced liver injury(DILI) Idiosyncratic DILI

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

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Cellular & Molecular Immunology 2016年第2期13卷 206-216页

作者： Stephanie Mathews Dechun Feng Igor Maricic cynthia ju Vipin Kumar Bin Gao Laboratory of Liver Diseases National institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda MD USA Laboratory of Autoimmunity Torrey Pines Institute for Molecular Studies San Diego CA USA Skaggs School of Pharmacy and Pharmaceutical Sciences and Integrated Immunology University of Colorado Anschutz Medical Campus Aurora CO USA

Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T （iNKT） cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice （CDld- and Ja18-deficient mice） were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone, iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines （e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin） involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CDld blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.

关键词： alcoholic hepatitis CDld inflammation liver

Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners

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Cellular & Molecular Immunology 2021年第9期18卷 2165-2176页

作者： Yeni Ait Ahmed Yaojie Fu Robim M.Rodrigues Yong He Yukun Guan Adrien Guillot Ruixue Ren Dechun Feng juan Hidalgo cynthia ju Fouad Lafdil Bin Gao Laboratory of Liver Diseases National Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthBethesdaMDUSA UniversitéParis-Est-Créteil CréteilFrance Universitat Autònoma de Barcelona BarcelonaSpain Department of Anesthesiology McGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTXUSA INSERM U955 Institut Mondor de Recherche BiomédicaleCréteilFrance Institut Universitaire de France(IUF) ParisFrance

Kupffer cells(KCs),which are liver-resident macrophages,originate from the fetal yolk sac and represent one of the largest macrophage populations in the ***,the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain ***,we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy(PHx)and uncover the underlying *** using several strains of genetically modified mice and performing immunohistochemical analyses,we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after *** KC proliferation was impaired in Il6-knockout(KO)mice and restored after the administration of IL-6 protein,whereas KC proliferation was not affected in Il4-KO or Csf2-KO *** source of IL-6 was identified using hepatocyte-and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after ***,peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx,suggesting that IL-6 signaling directly promotes KC *** using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1(SIRT1)contributed to IL-6-mediated KC proliferation in *** deletion of the Sirt1 gene in myeloid cells,including KCs,impaired KC proliferation after *** conclusion,our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation,which is dependent on IL-6 and SIRT1 activation in KCs.

关键词： IL-6 Sirtuin 1 Liver regeneration Kupffer cells Myeloid cells

The correlation between rat retinal nerve fiber layer thickness around optic disc by using optical coherence tomography and histological measurements

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International Journal of Ophthalmology(English edition) 2013年第4期6卷 415-421页

作者： ju-Fang Huang Hui-Min Yu Lei Shang Ruo-Fei Ma Ngobe Akume cynthia Yan-Qun Cao Jia Luo Le-Ping Zeng Dan Chen Kun Xiong Department of Anatomy and Neurobiology Central South University School of Basic Medical Sciences Department of Ophthalmology Central South University Third Xiangya Hospital Central South University Xiangya School of Medicine Department of Anatomy Shaoyang Medical College

·AIM: To explore the correlation between the retinal nerve fiber layer (RNFL) thickness by using optical coherence tomography (OCT) and by histological measurements in normal adult rats and optic nerve transected rats. · METHODS: The RNFL thickness of 36 rats was scanned in a circle 3.46mm far from the optic disc by OCT. The two experimental groups were the normal group ( =20 rats) and the optic nerve transected group ( =16 rats). The latter group included 4 groups ( =4 /group) surviving for 1 day, 3, 5 and 7 days. Then the RNFL thickness of the same retina area was also measured by NF -200 immunohistochemical staining method. Linear regression was used to analyze the correlation between the data obtained from these two methods. ·RESULTS: The RNFL thickness of normal right eyes around optic disc by OCT was 72.35 ±5.71μm and that of the left eyes was 72.65 ±5.88μm ( =0.074). The RNFL thickness of the corresponding histological section by immunohistochemistry was 37.54 ±4.05μm (right eyes) and 37.38 ±4.23μm (left eyes) ( =0.059). There was a good correlation between the RNFL thickness measured by OCT and that measured by histology (R 2 =0.8131). After optic nerve transection, the trend of the RNFL thickness was thinner with the prolonged survival time. The correlation of the thickness detected by the above two methods was approximately (R 2 =0.8265). Value of the RNFL thickness in rats around optic disc measured by OCT was obviously higher than that measured by common histological measurement in normal adult rats and optic nerve transected rats. ·CONCLUSION: The RNFL thickness measured by OCT has a strong correlation with that measured by histological method. Through OCT scanning, we found that the thickness of RNFL gradually becomes thinner in a time-dependent manner.

关键词： retinal nerve fiber layer thickness optical coherence tomography optic nerve transection immunohistochemistry staining relevance analysis rat

女性主义叙事学视域下《罗莎》中主人公的后大屠杀意识探究

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浙江外国语学院学报 2021年第2期 107-112页

作者：曲涛巨萱雅大连外国语大学英语学院辽宁大连116044

美国杰出犹太裔作家辛西娅·欧芝克的中篇小说《罗莎》讲述了丧女的大屠杀幸存者罗莎在后大屠杀时代的创伤体验,以及她如何在他人的帮助下逐渐走出创伤梦魇、摆脱自我认同危机。小说叙事形式别具一格,作家一改传统犹太写作将男性置于叙... 详细信息

美国杰出犹太裔作家辛西娅·欧芝克的中篇小说《罗莎》讲述了丧女的大屠杀幸存者罗莎在后大屠杀时代的创伤体验,以及她如何在他人的帮助下逐渐走出创伤梦魇、摆脱自我认同危机。小说叙事形式别具一格,作家一改传统犹太写作将男性置于叙事中心的常规,将叙事聚焦于女性人物罗莎战后的创伤体验;通过多重叙述声音讲述犹太女性的身份焦虑;变换叙述距离体现情感建构过程,增强叙事张力。基于女性主义叙事学理论,本文通过叙述视角、叙述声音和叙述距离三个层面探讨作家如何在后大屠杀时代建构犹太女性的话语权威,突显女性主体意识,以及作家选择特定叙述技巧的社会历史原因,以期从新的角度探讨小说的主题意蕴。

关键词：《罗莎》女性主义叙事学后大屠杀意识创伤身份焦虑