Full Text:   <1399>

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CLC number: R575.3

On-line Access: 2020-09-07

Received: 2020-05-13

Revision Accepted: 2020-07-20

Crosschecked: 2020-08-17

Cited: 0

Clicked: 2196

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Zhi Chen

https://orcid.org/0000-0002-0848-1502

Shu-jing Lai

https://orcid.org/0000-0003-3455-3300

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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.9 P.727-739

http://doi.org/10.1631/jzus.B2000249


Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner


Author(s):  Jing-wen Deng, Qin Yang, Xiao-peng Cai, Jia-ming Zhou, Wei-gao E, Yan-dong An, Qiu-xian Zheng, Meng Hong, Yan-li Ren, Jun Guan, Gang Wang, Shu-jing Lai, Zhi Chen

Affiliation(s):  State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; more

Corresponding email(s):   laishujing1@163.com, zjuchenzhi@zju.edu.cn

Key Words:  Glucocorticoid, Dexamethasone, Kupffer cells, Acute liver failure, Nuclear receptor subfamily 4 group A member 1 (Nr4a1)


Jing-wen Deng, Qin Yang, Xiao-peng Cai, Jia-ming Zhou, Wei-gao E, Yan-dong An, Qiu-xian Zheng, Meng Hong, Yan-li Ren, Jun Guan, Gang Wang, Shu-jing Lai, Zhi Chen. Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner[J]. Journal of Zhejiang University Science B, 2020, 21(9): 727-739.

@article{title="Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner",
author="Jing-wen Deng, Qin Yang, Xiao-peng Cai, Jia-ming Zhou, Wei-gao E, Yan-dong An, Qiu-xian Zheng, Meng Hong, Yan-li Ren, Jun Guan, Gang Wang, Shu-jing Lai, Zhi Chen",
journal="Journal of Zhejiang University Science B",
volume="21",
number="9",
pages="727-739",
year="2020",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2000249"
}

%0 Journal Article
%T Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner
%A Jing-wen Deng
%A Qin Yang
%A Xiao-peng Cai
%A Jia-ming Zhou
%A Wei-gao E
%A Yan-dong An
%A Qiu-xian Zheng
%A Meng Hong
%A Yan-li Ren
%A Jun Guan
%A Gang Wang
%A Shu-jing Lai
%A Zhi Chen
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 9
%P 727-739
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000249

TY - JOUR
T1 - Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner
A1 - Jing-wen Deng
A1 - Qin Yang
A1 - Xiao-peng Cai
A1 - Jia-ming Zhou
A1 - Wei-gao E
A1 - Yan-dong An
A1 - Qiu-xian Zheng
A1 - Meng Hong
A1 - Yan-li Ren
A1 - Jun Guan
A1 - Gang Wang
A1 - Shu-jing Lai
A1 - Zhi Chen
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 9
SP - 727
EP - 739
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000249


Abstract: 
Background and objective: acute liver failure (ALF) is a type of disease with high mortality and rapid progression with no specific treatment methods currently available. glucocorticoids exert beneficial clinical effects on therapy for ALF. However, the mechanism of this effect remains unclear and when to use glucocorticoids in patients with ALF is difficult to determine. The purpose of this study was to investigate the specific immunological mechanism of dexamethasone (Dex) on treatment of ALF induced by lipopolysaccharide (LPS)/D-galactosamine (D-GaIN) in mice. Methods: Male C57BL/6 mice were given LPS and D-GaIN by intraperitoneal injection to establish an animal model of ALF. Dex was administrated to these mice and its therapeutic effect was observed. Hematoxylin and eosin (H&E) staining was used to determine liver pathology. Multicolor flow cytometry, cytometric bead array (CBA) method, and next-generation sequencing were performed to detect changes of messenger RNA (mRNA) in immune cells, cytokines, and kupffer cells, respectively. Results: A mouse model of ALF can be constructed successfully using LPS/D-GaIN, which causes a cytokine storm in early disease progression. Innate immune cells change markedly with progression of liver failure. Earlier use of Dex, at 0 h rather than 1 h, could significantly improve the progression of ALF induced by LPS/D-GaIN in mice. Numbers of innate immune cells, especially kupffer cells and neutrophils, increased significantly in the Dex-treated group. In vivo experiments indicated that the therapeutic effect of Dex is exerted mainly via the glucocorticoid receptor (Gr). Sequencing of kupffer cells revealed that Dex could increase mRNA transcription level of nuclear receptor subfamily 4 group A member 1 (Nr4a1), and that this effect disappeared after Gr inhibition. Conclusions: In LPS/D-GaIN-induced ALF mice, early administration of Dex improved ALF by increasing the numbers of innate immune cells, especially kupffer cells and neutrophils. Gr-dependent Nr4a1 upregulation in kupffer cells may be an important ALF effect regulated by Dex in this process.

早期使用地塞米松可通过糖皮质激素受体依赖的方式促进Kupffer中Nr4a1表达来改善小鼠急性肝衰竭

目的:本研究旨在明确地塞米松(Dex)对脂多糖/D-半乳糖胺(LPS/D-GaIN)诱导的急性肝衰竭(ALF)小鼠的治疗效果,并探讨其发挥作用的免疫学机制.
创新点:首次发现,早期使用Dex对LPS/D-GaIN诱导的小鼠ALF具有较好的治疗效果,库普佛(Kupffer)细胞在该过程中发挥重要的作用.
方法:C57BL/6小鼠通过LPS/D-GaIN腹腔注射诱导建立小鼠ALF模型,然后不同时间点予以Dex,观察其治疗效果.使用糖皮质激素受体(Gr)抑制剂检测其具体作用机制;通过血清肝酶检测和苏木素-伊红(H&E)染色明确肝脏损伤情况;使用多色流式细胞术检测肝脏和血液免疫细胞变化;使用流式微珠阵列(CBA)法检测小鼠血清细胞因子变化;使用二代测序检测小鼠Kupffer细胞信使RNA(mRNA)变化.
结论:早期使用Dex可增加小鼠肝脏Kupffer细胞数目,并促进Kupffer细胞中Nr4a1表达,从而改善LPS/D-GaIN诱导的小鼠ALF.

关键词:糖皮质激素;地塞米松;库普佛细胞;急性肝衰竭;Nr4a1

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]Achuthan A, Aslam ASM, Nguyen Q, et al., 2018. Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity. Cell Death Dis, 9(3):267.

[2]Bao SX, Zheng JM, Li N, et al., 2017. Role of interleukin-23 in monocyte-derived dendritic cells of HBV-related acute-on-chronic liver failure and its correlation with the severity of liver damage. Clin Res Hepatol Gastroenterol, 41(2):147-155.

[3]Bernal W, Auzinger G, Dhawan A, et al., 2010. Acute liver failure. Lancet, 376(9736):190-201.

[4]Bonta PI, van Tiel CM, Vos M, et al., 2006. Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses. Arterioscler Thromb Vasc Biol, 26(10):2288.

[5]Cain DW, Cidlowski JA, 2017. Immune regulation by glucocorticoids. Nat Rev Immunol, 17(4):233-247.

[6]Carpenter MD, Hu QW, Bond AM, et al., 2020. Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes. Nat Commun, 11(1):504.

[7]CMA (Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association), 2019. Guideline for diagnosis and treatment of liver failure. Chin J Hepatol, 27(1):18-26 (in Chinese).

[8]Fujiwara K, Yasui S, Yonemitsu Y, et al., 2014. Efficacy of high-dose corticosteroid in the early stage of viral acute liver failure. Hepatol Res, 44(5):491-501.

[9]Gagliano T, Shah K, Gargani S, et al., 2020. PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression. J Clin Invest, 130(6):3188-3204.

[10]Garabuczi E, Sarang Z, Szondy Z, 2015. Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator- activated receptor-δ and UCP2. Biochim Biophys Acta, 1853(3):573-582.

[11]Hanna RN, Carlin LM, Hubbeling HG, et al., 2011. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C-monocytes. Nat Immunol, 12(8):778-785.

[12]Heideveld E, Hampton-O'Neil LA, Cross SJ, et al., 2018. Glucocorticoids induce differentiation of monocytes towards macrophages that share functional and phenotypical aspects with erythroblastic island macrophages. Haematologica, 103(3):395-405.

[13]Honda M, Surewaard BGJ, Watanabe M, et al., 2020. Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome. Nat Commun, 11(1):1329.

[14]Joshi N, Kopec AK, Ray JL, et al., 2016. Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism. Blood, 127(22):2751-2762.

[15]Kakisaka K, Kataoka K, Suzuki Y, et al., 2017. Appropriate timing to start and optimal response evaluation of high-dose corticosteroid therapy for patients with acute liver failure. J Gastroenterol, 52(8):977-985.

[16]Karkhanis J, Verna EC, Chang MS, et al., 2014. Steroid use in acute liver failure. Hepatology, 59(2):612-621.

[17]Leroux A, Ferrere G, Godie V, et al., 2012. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol, 57(1):141-149.

[18]Lewis PS, Campana L, Aleksieva N, et al., 2020. Alternatively activated macrophages promote resolution of necrosis following acute liver injury. J Hepatol, 73(2):349-360.

[19]Lyu C, Shi QL, Qin Q, et al., 2019. A review of experimental liver injury models in mice. Chin J Comp Med, 29(1):107-113 (in Chinese).

[20]Panettieri RA, Schaafsma D, Amrani Y, et al., 2019. Non-genomic effects of glucocorticoids: an updated view. Trends Pharmacol Sci, 40(1):38-49.

[21]Possamai LA, Thursz MR, Wendon JA, et al., 2014. Modulation of monocyte/macrophage function: a therapeutic strategy in the treatment of acute liver failure. J Hepatol, 61(2):439-445.

[22]Robert O, Boujedidi H, Bigorgne A, et al., 2016. Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice. J Hepatol, 64(4):916-924.

[23]Scheving LA, Buchanan R, Krause MA, et al., 2007. Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes. Am J Physiol Gastrointest Liver Physiol, 293(3):G552-G559.

[24]Stravitz RT, Lee WM, 2019. Acute liver failure. Lancet, 394(10201):869-881.

[25]Tuckermann JP, Kleiman A, Moriggl R, et al., 2007. Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J Clin Invest, 117(5):1381-1390.

[26]Valdez R, Cavinder CA, Varner DD, et al., 2019. Dexamethasone downregulates expression of several genes encoding orphan nuclear receptors that are important to steroidogenesis in stallion testes. J Biochem Mol Toxicol, 33(6):e22309.

[27]van de Garde MDB, Martinez FO, Melgert BN, et al., 2014. Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction. J Immunol, 192(3):1196-1208.

[28]Wang HJ, Xu X, Guan X, et al., 2020. Liposomal 9-aminoacridine for treatment of ischemic stroke: from drug discovery to drug delivery. Nano Lett, 20(3):1542-1551.

[29]Wang K, Wu ZB, Ye YN, et al., 2014. Plasma interleukin-10: a likely predictive marker for hepatitis B virus-related acute-on-chronic liver failure. Hepat Mon, 14(7):e19370.

[30]Yu WQ, Zhang SY, Fu SQ, et al., 2019. Dexamethasone protects the glycocalyx on the kidney microvascular endothelium during severe acute pancreatitis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(4):355-362.

[31]Zhao HL, Han QJ, Lu N, et al., 2018. HMBOX1 in hepatocytes attenuates LPS/D-GalN-induced liver injury by inhibiting macrophage infiltration and activation. Mol Immunol, 101:303-311.

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