黑色素瘤缺乏因子2在肝脏疾病中的作用机制及临床意义

乐滢玉; 张荣臻; 王挺帅; 陈宁芳; 毛德文

doi:10.3969/j.issn.1001-5256.2021.10.049

黑色素瘤缺乏因子2在肝脏疾病中的作用机制及临床意义

DOI: 10.3969/j.issn.1001-5256.2021.10.049

1.
广西中医药大学研究生院，南宁 530222
2a.
广西中医药大学第一附属医院肝病一区，南宁 530023
2b.
广西中医药大学第一附属医院脾胃一区，南宁 530023

基金项目:

国家自然科学基金面上项目 (81774236);

国家自然科学基金项目 (81960841);

广西自然科学基金课题 (2018GXNSFAA281096);

广西科技计划项目-广西科技基地和人才专项 (GK AD17129001)

详细信息

通信作者:
毛德文，mdwboshi2005@163.com

中图分类号: R575
计量
- 文章访问数: 324
- HTML全文浏览量: 93
- PDF下载量: 24
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-03
- 录用日期: 2021-03-15
- 出版日期: 2021-10-20

Expression mechanism and clinical significance of absent in melanoma 2 in liver diseases

1.
Graduate School, Guangxi University of Chinese Medicine, Nanning 530222, China
2a.
First Ward of Liver Diseases, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China
2b.
First Ward of Spleen and Stomach, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China

Research funding:

General Project of National Natural Science Foundation of China (81774236);

National Natural Science Foundation of China (81960841);

Natural Science Foundation of Guangxi Province (2018GXNSFAA281096);

Guangxi Science and Technology Plan Project-Guangxi Science and Technology Base and Talent Special Project (GK AD17129001)

摘要

摘要: 黑色素瘤缺乏因子2(AIM2)是细胞质双链DNA感应蛋白，可识别在细胞扰动和病原体侵袭期间释放的双链DNA，并触发炎性体级联反应的激活。炎性体的激活会导致炎性细胞因子(IL-1β、IL-18)的成熟释放，并诱导细胞焦亡，启动固有免疫应答。其中，炎性小体AIM2在肝脏疾病中的作用机理及其临床意义已日趋成为当下研究的热点，现就AIM2在非酒精性脂肪性肝病、HBV感染、肝纤维化、肝硬化和肝细胞癌等肝脏疾病发病机制中的重要性进行归纳和探讨，以期为其临床治疗提供新的思路和参考。
- 肝疾病 /
- 炎症 /
- 炎性体
Abstract: Absent in melanoma 2 (AIM2) is a cytoplasmic double-stranded DNA (dsDNA) sensing protein that can recognize the dsDNA released during cell disturbance and pathogen invasion and trigger the activation of inflammasome cascade. Activation of inflammasomes leads to the maturation and release of inflammatory cytokines (interleukin-1β and interleukin-18), induces pyroptosis, and initiate innate immune response. Among these inflammasomes, AIM2 and its mechanism of action and clinical significance in liver diseases has become a research hotspot at present. This article summarizes and discusses the importance of AIM2 in the pathogenesis of various liver diseases including nonalcoholic fatty liver disease, hepatitis B virus infection, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, so as to provide new ideas and a reference for clinical treatment.
- Liver Diseases /
- Inflammation /
- Inflammasomes

HTML全文

参考文献(42)

[1]	NEWTON K, DIXIT VM. Signaling in innate immunity and inflammation[J]. Cold Spring Harb Perspect Biol, 2012, 4(3): a006049. DOI: 10.1101/cshperspect.a006049.
[2]	TAKEUCHI O, AKIRA S. Pattern recognition receptors and inflammation[J]. Cell, 2010, 140(6): 805-820. DOI: 10.1016/j.cell.2010.01.022.
[3]	SZABO G, PETRASEK J. Inflammasome activation and function in liver disease[J]. Nat Rev Gastroenterol Hepatol, 2015, 12(7): 387-400. DOI: 10.1038/nrgastro.2015.94.
[4]	SHI C, YANG H, ZHANG Z. Involvement of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 inflammasome in the pathogenesis of liver diseases[J]. Front Cell Dev Biol, 2020, 8: 139. DOI: 10.3389/fcell.2020.00139.
[5]	XU T, DU Y, FANG XB, et al. New insights into Nod-like receptors (NLRs) in liver diseases[J]. Int J Physiol Pathophysiol Pharmacol, 2018, 10(1): 1-16. http://www.ijppp.org/files/ijppp0073857.pdf
[6]	SZABO G, CSAK T. Inflammasomes in liver diseases[J]. J Hepatol, 2012, 57(3): 642-654. DOI: 10.1016/j.jhep.2012.03.035.
[7]	LUAN J, JU D. Inflammasome: A double-edged sword in liver diseases[J]. Front Immunol, 2018, 9: 2201. DOI: 10.3389/fimmu.2018.02201.
[8]	JIN T, PERRY A, JIANG J, et al. Structures of the HIN domain: DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor[J]. Immunity, 2012, 36(4): 561-571. DOI: 10.1016/j.immuni.2012.02.014.
[9]	WANG B, YIN Q. AIM2 inflammasome activation and regulation: A structural perspective[J]. J Struct Biol, 2017, 200(3): 279-282. DOI: 10.1016/j.jsb.2017.08.001.
[10]	MORRONE SR, MATYSZEWSKI M, YU X, et al. Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC[J]. Nat Commun, 2015, 6: 7827. DOI: 10.1038/ncomms8827.
[11]	HOSS F, RODRIGUEZ-ALCAZAR JF, LATZ E. Assembly and regulation of ASC specks[J]. Cell Mol Life Sci, 2017, 74(7): 1211-1229. DOI: 10.1007/s00018-016-2396-6.
[12]	LIU X, ZHANG Z, RUAN J, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores[J]. Nature, 2016, 535(7610): 153-158. DOI: 10.1038/nature18629.
[13]	BROZ P, DIXIT VM. Inflammasomes: Mechanism of assembly, regulation and signalling[J]. Nat Rev Immunol, 2016, 16(7): 407-420. DOI: 10.1038/nri.2016.58.
[14]	YANG J, LIU Z, XIAO TS. Post-translational regulation of inflammasomes[J]. Cell Mol Immunol, 2017, 14(1): 65-79. DOI: 10.1038/cmi.2016.29.
[15]	LIU T, TANG Q, LIU K, et al. TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent selective autophagy[J]. Cell Rep, 2016, 16(7): 1988-2002. DOI: 10.1016/j.celrep.2016.07.019.
[16]	KHARE S, RATSIMANDRESY RA, de ALMEIDA L, et al. The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses[J]. Nat Immunol, 2014, 15(4): 343-353. DOI: 10.1038/ni.2829.
[17]	LI H, WANG J, WANG J, et al. Structural mechanism of DNA recognition by the p202 HINa domain: Insights into the inhibition of Aim2-mediated inflammatory signalling[J]. Acta Crystallogr F Struct Biol Commun, 2014, 70(Pt 1): 21-29. DOI: 10.1107/S2053230X1303135X.
[18]	YIN Q, SESTER DP, TIAN Y, et al. Molecular mechanism for p202-mediated specific inhibition of AIM2 inflammasome activation[J]. Cell Rep, 2013, 4(2): 327-339. DOI: 10.1016/j.celrep.2013.06.024.
[19]	DIEHL AM, FARPOUR-LAMBERT NJ, ZHAO L, et al. Why we need to curb the emerging worldwide epidemic of nonalcoholic fatty liver disease[J]. Nat Metab, 2019, 1(11): 1027-1029. DOI: 10.1038/s42255-019-0140-x.
[20]	CSAK T, PILLAI A, GANZ M, et al. Both bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis[J]. Liver Int, 2014, 34(9): 1402-1413. DOI: 10.1111/liv.12537.
[21]	TANG D, KANG R, ZEH HJ 3rd, et al. High-mobility group box 1, oxidative stress, and disease[J]. Antioxid Redox Signal, 2011, 14(7): 1315-1335. DOI: 10.1089/ars.2010.3356.
[22]	GANZ M, CSAK T, SZABO G. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation[J]. World J Gastroenterol, 2014, 20(26): 8525-8534. DOI: 10.3748/wjg.v20.i26.8525.
[23]	GONG Z, ZHANG X, SU K, et al. Deficiency in AIM2 induces inflammation and adipogenesis in white adipose tissue leading to obesity and insulin resistance[J]. Diabetologia, 2019, 62(12): 2325-2339. DOI: 10.1007/s00125-019-04983-x.
[24]	Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B(version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007.
[25]	PANG XQ, LI XH, MO ZS, et al. Expression of factor 2 deficiency in patients with chronic hepatitis B and its correlation with the degree of disease[J/CD]. Chin J Exp Clin Infect Dis (Electronic Edition), 2015, 9(3): 326-330. DOI: 10.3877/cma.j.issn.1674-1358.2015.03.007. 庞秀青, 李新华, 莫志硕, 等. 慢性乙型肝炎患者肝组织中黑色素瘤缺乏因子2表达与病变程度的相关性[J/CD]. 中华实验和临床感染病杂志(电子版), 2015, 9(3): 326-330. DOI: 10.3877/cma.j.issn.1674-1358.2015.03.007.
[26]	WU DL, XU GH, LU SM, et al. Correlation of AIM2 expression in peripheral blood mononuclear cells from humans with acute and chronic hepatitis B[J]. Hum Immunol, 2013, 74(5): 514-521. DOI: 10.1016/j.humimm.2013.01.022.
[27]	CHEN H, HE G, CHEN Y, et al. Differential activation of NLRP3, AIM2, and IFI16 inflammasomes in humans with acute and chronic hepatitis B[J]. Viral Immunol, 2018, 31(9): 639-645. DOI: 10.1089/vim.2018.0058.
[28]	HAN Y, CHEN Z, HOU R, et al. Expression of AIM2 is correlated with increased inflammation in chronic hepatitis B patients[J]. Virol J, 2015, 12: 129. DOI: 10.1186/s12985-015-0360-y.
[29]	ZHEN J, ZHANG L, PAN J, et al. AIM2 mediates inflammation-associated renal damage in hepatitis B virus-associated glomerulonephritis by regulating caspase-1, IL-1β, and IL-18[J]. Mediators Inflamm, 2014, 2014: 190860. DOI: 10.1155/2014/190860.
[30]	NORDSTRÖM A, BERGMAN J, BJÖRK S, et al. A multiple risk factor program is associated with decreased risk of cardiovascular disease in 70-year-olds: A cohort study from Sweden[J]. PLoS Med, 2020, 17(6): e1003135. DOI: 10.1371/journal.pmed.1003135.
[31]	CIGROVSKI BERKOVIC M, VIROVIC-JUKIC L, BILIC-CURCIC I, et al. Post-transplant diabetes mellitus and preexisting liver disease - a bidirectional relationship affecting treatment and management[J]. World J Gastroenterol, 2020, 26(21): 2740-2757. DOI: 10.3748/wjg.v26.i21.2740.
[32]	GIESECK RL 3rd, WILSON MS, WYNN TA. Type 2 immunity in tissue repair and fibrosis[J]. Nat Rev Immunol, 2018, 18(1): 62-76. DOI: 10.1038/nri.2017.90.
[33]	LOZANO-RUIZ B, BACHILLER V, GARCÍA-MARTÍNEZ I, et al. Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosis[J]. J Hepatol, 2015, 62(1): 64-71. DOI: 10.1016/j.jhep.2014.08.027.
[34]	GONZÁLEZ-NAVAJAS JM. Inflammasome activation in decompensated liver cirrhosis[J]. World J Hepatol, 2016, 8(4): 207-210. DOI: 10.4254/wjh.v8.i4.207.
[35]	ARRIOLA BENITEZ PC, PESCE VIGLIETTI AI, GOMES M, et al. Brucella abortus infection elicited hepatic stellate cell-mediated fibrosis through inflammasome-dependent IL-1β production[J]. Front Immunol, 2019, 10: 3036. DOI: 10.3389/fimmu.2019.03036.
[36]	CHEN T, CHENG PC, CHANG KC, et al. Activation of the NLRP3 and AIM2 inflammasomes in a mouse model of Schistosoma mansoni infection[J]. J Helminthol, 2019, 94: e72. DOI: 10.1017/S0022149X19000622.
[37]	National Health Commission of the People's Republic of China Medical Administration and Medical Administration. Guidelines for diagnosis and treatment of primary liver cancer (Versoin 2019)[J]. J Clin Hepatol, 2020, 36(2): 277-292. DOI: 10.3969/j.issn.1001-5256.2020.02.007. 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版)[J]. 临床肝胆病杂志, 2020, 36(2): 277-292. DOI: 10.3969/j.issn.1001-5256.2020.02.007.
[38]	MA XM, QIU YM, MA XX, et al. AIM2 inhibits the progression of hepatocellular carcinoma through the formation and activation of inflammasomes[C]. Chinese Society of Immunology, 2016: 227-228. 马小敏, 邱驭旻, 马晓晓, 等. AIM2通过炎症小体的形成与活化抑制肝细胞肝癌的进展[C]. 中国免疫学会, 2016: 227-228.
[39]	CHEN HT, YANG Z, WU SP. Expression and clinical significance of factor 2 deficiency in peripheral blood mononuclear cell melanoma in primary liver cancer[J/CD]. Electronic Journal of Emerging Infectious Diseases, 2019, 4(3): 149-151, 168. 陈洪涛, 杨智, 吴诗品. 外周血单个核细胞黑色素瘤缺乏因子2在原发性肝癌中的表达及其临床意义[J/CD]. 新发传染病电子杂志, 2019, 4(3): 149-151, 168.
[40]	CHEN SL, LIU LL, LU SX, et al. HBx-mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis[J]. Mol Oncol, 2017, 11(9): 1225-1240. DOI: 10.1002/1878-0261.12090.
[41]	MA X, GUO P, QIU Y, et al. Loss of AIM2 expression promotes hepatocarcinoma progression through activation of mTOR-S6K1 pathway[J]. Oncotarget, 2016, 7(24): 36185-36197. DOI: 10.18632/oncotarget.9154.
[42]	MARTÍNEZ-CARDONA C, LOZANO-RUIZ B, BACHILLER V, et al. AIM2 deficiency reduces the development of hepatocellular carcinoma in mice[J]. Int J Cancer, 2018, 143(11): 2997-3007. DOI: 10.1002/ijc.31827.