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Hepatic macrophage-targeted therapy for fatty liver disease: Opportunities and challenges
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摘要:
肝巨噬细胞是天然免疫系统中的重要组分,在生理环境下识别、清除坏死或凋亡的细胞碎片、病原体、呈递抗原,参与适应性免疫及免疫监视;在病理状态下,激活的巨噬细胞产生和释放大量炎性因子和细胞因子,并募集其他免疫细胞到局部参与抗感染或组织修复,是脂肪性肝病的重要发病机制及疾病进展的关键因素。作为肝脏免疫细胞的重要组分,肝巨噬细胞因子在疾病发病机制中的核心作用、以及基于肝巨噬细胞的靶向治疗而受到关注。综述了肝巨噬细胞靶向治疗脂肪性肝病及其面临的挑战和机遇。
Abstract:Hepatic macrophages are an important cell component in the natural immune system. In the physiological environment,they can recognize and eliminate necrotic or apoptotic cell fragments,pathogens,and presenting antigens and participate in adaptive immunity and immune surveillance,while in the pathological state,activated macrophages can produce and release a large number of inflammatory factors and cytokines and recruit other immune cells to participate in local anti-infection or tissue repair,and therefore,they are the key factor in the pathogenesis and progression of fatty liver disease. As an important component of hepatic immune cells,hepatic macrophages have attracted great attention due to its role in the pathogenesis of the disease and the hepatic macrophage-targeted therapy. This article reviews the challenges and opportunities in hepatic macrophage-targeted therapy for fatty liver disease.
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Key words:
- fatty liver /
- macrophages /
- molecular targeted therapy
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[1] CHA JY,KIM DH,CHUN KH. The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Lab Anim Res,2018,34(4):133-139. [2] ABDULLAH Z,KNOLLE PA. Liver macrophages in healthy and diseased liver[J]. Pflugers Arch,2017,469(3-4):553-560. [3] WANG LX,ZHANG SX,WU HJ,et al. M2b macrophage polarization and its roles in diseases[J]. J Leukoc Biol,2019,106(2):345-358. [4] BAECK C,WEHR A,KARLMARK KR,et al. Pharmacological inhibition of the chemokine CCL2(MCP-1)diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury[J]. Gut,2012,61(3):416-426. [5] van der HEIDE D,WEISKIRCHEN R,BANSAL R. Therapeutic targeting of hepatic macrophages for the treatment of liver diseases[J]. Front Immunol,2019,10:2852. [6] CARPINO G,del BEN M,PASTORI D,et al. Increased liver localization of lipopolysaccharides in human and experimental non-alcoholic fatty liver disease[J]. Hepatology,2019.[Online ahead of print] [7] KRENKEL O,HUNDERTMARK J,ABDALLAH AT,et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis[J]. Gut,2020,69(3):551-563. [8] XIONG X,KUANG H,ANSARI S,et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by singlecell secretome gene analysis[J]. Mol Cell,2019,75(3):644-660. e5. [9] LI L,WEI W,LI Z,et al. The spleen promotes the secretion of CCL2 and supports an M1 dominant phenotype in hepatic macrophages during liver fibrosis[J]. Cell Physiol Biochem,2018,51(2):557-574. [10] LOOMBA R,LAWITZ E,MANTRY PS,et al. GS-4997,an inhibitor of apoptosis signal-regulating kinase(ASK1),alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis(NASH):A randomized,phase 2 trial[J]. Hepatology,2016,64(Suppl):1119A-1120A. [11] GUAL P,GILGENKRANTZ H,LOTERSZTAJN S. Autophagy in chronic liver diseases:The two faces of Janus[J]. Am J Physiol Cell Physiol,2017,312(3):C263-C273. [12] DUITS D,WELLENSTEIN MD,de VISSER KE. In vitro assessment of cancer cell-induced polarization of macrophages[J]. Methods Enzymol,2020,632:133-154. [13] YAO RR,LI JH,ZHANG R,et al. M2-polarized tumor-associated macrophages facilitated migration and epithelialmesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway[J]. World J Surg Oncol,2018,16(1):9. [14] LI X,YAO W,YUAN Y,et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma[J]. Gut,2017,66(1):157-167. [15] PIERANTONELLI L,RYCHLICKI C,AGOSTINELLI L,et al. Lack of NLRP3-inflammasome leads to gut-liver axis derangement,gut dysbiosis and a worsened phenotype in a mouse model of NAFLD[J]. Sci Rep,2017,7(1):12200. [16] WANG Q,WEI S,ZHOU S,et al. Hyperglycemia aggravates acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via the inhibition of AMPK/mTOR-mediated autophagy induction[J]. Immunol Cell Biol,2020,98(1):54-66. [17] LOOMBA R,LAWITZ E,MANTRY PS,et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis:A randomized,phase 2 trial[J]. Hepatology,2018,67(2):549-559. [18] MARADANA MR,YEKOLLU SK,ZENG B,et al. Immunomodulatory liposomes targeting liver macrophages arrest progression of nonalcoholic steatohepatitis[J]. Metabolism,2018,78:80-94. [19] FREUND B,HEEREN J,NIELSEN P,et al. Nanoparticle compositions for generation of regulatory T cells and treatment of autoimmune diseases and other chronic inflammatory conditions[EB/OL]. http://www. freepatentsonline. com/y2018/0325821. html. [20] KURNIAWAN DW,JAJORIYA AK,DHAWAN G,et al. Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of nonalcoholic steatohepatitis[J]. J Control Release,2018,288:227-238. [21] YU Y,LIU Y,AN W,et al. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis[J]. J Clin Invest,2019,129(2):546-555. [22] MASS E. Delineating the origins,developmental programs and homeostatic functions of tissue-resident macrophages[J]. Int Immunol,2018,30(11):493-501. [23] STUTCHFIELD BM,ANTOINE DJ,MACKINNON AC,et al.CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure[J]. Gastroenterology,2015,149(7):1896-1909. e14. [24] VONGHIA L,van HERCK MA,WEYLER J,et al. Targeting myeloid-derived cells:New frontiers in the treatment of non-alcoholic and alcoholic liver disease[J]. Front Immunol,2019,10:563. [25] WANG B,LI Q,QIN L,et al. Transition of tumor-associated macrophages from MHC class II(hi)to MHC class II(low)mediates tumor progression in mice[J]. BMC Immunol,2011,12:43. [26] ZHENG F,SPARKES A,de BAETSELIER P,et al. Molecular imaging with Kupffer cell-targeting nanobodies for diagnosis and prognosis in mouse models of liver pathogenesis[J]. Mol Imaging Biol,2017,19(1):49-58. [27] FANTUZZI L,TAGLIAMONTE M,GAUZZI MC,et al. Dual CCR5/CCR2 targeting:Opportunities for the cure of complex disorders[J]. Cell Mol Life Sci,2019,76(24):4869-4886. [28] AO JY,ZHU XD,CHAI ZT,et al. Colony-stimulating factor 1receptor blockade inhibits tumor growth by altering the polarization of tumor-associated macrophages in hepatocellular carcinoma[J]. Mol Cancer Ther,2017,16(8):1544-1554. [29] FANG P,XIANG L,HUANG S,et al. IRE1α-XBP1 signaling pathway regulates IL-6 expression and promotes progression of hepatocellular carcinoma[J]. Oncol Lett,2018,16(4):4729-4736. [30] FERNNDEZ-VARO G,PERRAMN M,CARVAJAL S,et al.Bespoken nanoceria:A new effective treatment in experimental hepatocellular carcinoma[J]. Hepatology,2020.[Online ahead of print] [31] MA HY,YAMAMOTO G,XU J,et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease[J]. J Hepatol,2019.[Online ahead of print] [32] GOMES AL,TEIJEIRO A,BURN S,et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma[J]. Cancer Cell,2016,30(1):161-175. [33] FOGLIA B,SUTTI S,PEDICINI D,et al. Oncostatin M,a profibrogenic mediator overexpressed in non-alcoholic fatty liver disease,stimulates migration of hepatic myofibroblasts[J].Cells,2019,9(1):28. [34] DONG B,ZHOU Y,WANG W,et al. Vitamin D receptor activation in liver macrophages ameliorates hepatic inflammation,steatosis,and insulin resistance in mice[J]. Hepatology,2019.[Online ahead of print] [35] SONG K,KWON H,HAN C,et al. Yes-associated protein in Kupffer cells enhances the production of proinflammatory cytokines and promotes the development of nonalcoholic steatohepatitis[J]. Hepatology,2019.[Online ahead of print] -
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