中性粒细胞胞外诱捕网在胃肠道中的应用
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摘要
中性粒细胞胞外诱捕网(neutrophil extracellulartraps,NETs)在感染过程中具有重要作用,它可以帮助中性粒细胞捕获和杀死病原体。然而,越来越多的证据表明,不受控制或过量的NETs与炎症的加剧和自身免疫的发展、癌症转移以及不适当的血栓形成有关。并进一步阐述NETs在胃肠系统中的作用,概述它们的保护机制和病理作用,讨论NETs形成的最新机制,微生物和NETs之间的相互作用以及中性粒细胞亚型与它们功能之间的关系。此外,NETs相关分子,包括游离DNA和超瓜氨酸化组蛋白等,可作为生物标志物和胃肠道疾病治疗干预的靶点。
Neutrophil extracellular traps(NETs) play an important role in the process of infection by helping neutrophils capture and kill pathogens. However, uncontrolled or excessive production of NETs is related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. The role of extracellular trapping nets of neutrophils in gastrointestinal system was further elaborated. Their protective mechanism and pathological role were summarized. The latest mechanism of NETs formation, the interaction between microorganisms and NETs, and the relationship between the subtypes of neutrophils and their functions were discussed. In addition, NETs-related molecules, including free DNA and hypercitrullinated histones, can be used as biomarkers and therapeutic targets for gastrointestinal diseases.
Neutrophil extracellular traps(NETs) play an important role in the process of infection by helping neutrophils capture and kill pathogens. However, uncontrolled or excessive production of NETs is related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. The role of extracellular trapping nets of neutrophils in gastrointestinal system was further elaborated. Their protective mechanism and pathological role were summarized. The latest mechanism of NETs formation, the interaction between microorganisms and NETs, and the relationship between the subtypes of neutrophils and their functions were discussed. In addition, NETs-related molecules, including free DNA and hypercitrullinated histones, can be used as biomarkers and therapeutic targets for gastrointestinal diseases.
引文
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[32] MALIK H Z,PRASAD K R,HALAZUN K J,et al.Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases [J].Ann Surg,2007,246(5):806-814.DOI:10.1097/SLA.0b013e318142d964.
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[35] MILLRUD C R,K?GEDAL ?,KUMLIEN GEORéN S,et al.NET-producing CD16high CD62Ldim neutrophils migrate to tumor sites and predict improved survival in patients with HNSCC [J].Int J Cancer,2017,140(11):2557-2567.DOI:10.1002/ijc.30671.
[36] TOHME S,YAZADANI H O,AL-KHAFAJI A B,et al.Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress [J].Cancer Res,2016,76(6):1367-1380.DOI:10.1158/0008-5472.CAN-15-1591.
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[41] BOONE B A,ORLICHENKO L,SCHAPIRO N E,et al.The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer [J].Cancer Gene Ther,2015,22(6):326-334.DOI:10.1038/cgt.2015.21.
[42] YANG C,SUN W,CUI W,et al.Procoagulant role of neutrophil extracellular traps in patients with gastric cancer [J].Int J Clin Exp Pathol,2015,8(11):14075-14086.
[43] ARELAKI S,ARAMPATZIOGLOU A,KAMBAS K,et al.Gradient infiltration of neutrophil extracellular traps in colon cancer and evidence for their involvement in tumour growth [J].PLoS One,2016,11(5):e0154484.DOI:10.1371/journal.pone.0154484.
[44] HWANG W L,LAN H Y,CHENG W C,et al.Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer [J].J Hematol Oncol,2019,12(1):10.DOI:10.1186/s13045-019-0699-4.
[45] ABDOL RAZAK N,ELASKALANI O,METHAROM P.Pancreatic cancer-induced neutrophil extracellular traps:a potential contributor to cancer-associated thrombosis [J].Int J Mol Sci,2017,18(3).pii:E487.DOI:10.3390/ijms18030487.
[46] HOSSEINZADEH A,THOMPSON P R,SEGAL B H,et al.Nicotine induces neutrophil extracellular traps [J].J Leukoc Biol,2016,100(5):1105-1112.DOI:10.1189/jlb.3AB0815-379RR.
[2] LI P,LI M,LINDBERG M R,et al.PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps [J].J Exp Med,2010,207(9):1853-1862.DOI:10.1084/jem.20100239.
[3] JORCH S K,KUBES P.An emerging role for neutrophil extracellular traps in noninfectious disease [J].Nat Med,2017,23(3):279-287.DOI:10.1038/nm.4294.
[4] LOOD C,BLANCO L P,PURMALEK M M,et al.Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease [J].Nat Med,2016,22(2):146-153.DOI:10.1038/nm.4027.
[5] WONG S L,DEMERS M,MARTINOD K,et al.Diabetes primes neutrophils to undergo NETosis,which impairs wound healing [J].Nat Med,2015,21(7):815-819.DOI:10.1038/nm.3887.
[6] FUCHS T A,BRILL A,DUERSCHMIED D,et al.Extracellular DNA traps promote thrombosis [J].Proc Natl Acad Sci U S A,2010,107(36):15880-15885.DOI:10.1073/pnas.1005743107.
[7] BENNIKE T B,CARLSEN T G,ELLINGSEN T,et al.Neutrophil extracellular traps in ulcerative colitis:a proteome analysis of intestinal biopsies [J].Inflamm Bowel Dis,2015,21(9):2052-2067.DOI:10.1097/MIB.0000000000000460.
[8] BRINKMANN V,REICHARD U,GOOSMANN C,et al.Neutrophil extracellular traps kill bacteria [J].Science,2004,303(5663):1532-1535.DOI:10.1126/science.1092385.
[9] TAKEI H,ARAKI A,WATANABE H,et al.Rapid killing of human neutrophils by the potent activator phorbol 12-myristate 13-acetate (PMA) accompanied by changes different from typical apoptosis or necrosis [J].J Leukoc Biol,1996,59(2):229-240.DOI:10.1002/jlb.59.2.229.
[10] YIPP B G,PETRI B,SALINA D,et al.Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo [J].Nat Med,2012,18(9):1386-1393.DOI:10.1038/nm.2847.
[11] BYRD A S,O′BRIEN X M,JOHNSON C M,et al.An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans [J].J Immunol,2013,190(8):4136-4148.DOI:10.4049/jimmunol.1202671.
[12] M?LLERHERM H,NEUMANN A,SCHILCHER K,et al.Yersinia enterocolitica-mediated degradation of neutrophil extracellular traps (NETs) [J].FEMS Microbiol Lett,2015,362(23):fnv192.DOI:10.1093/femsle/fnv192.
[13] CARESTIA A,KAUFMAN T,RIVADENEYRA L,et al.Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets [J].J Leukoc Biol,2016,99(1):153-162.DOI:10.1189/jlb.3A0415-161R.
[14] KHORUTS A,SADOWSKY M J.Understanding the mechanisms of faecal microbiota transplantation [J].Nat Rev Gastroenterol Hepatol,2016,13(9):508-516.DOI:10.1038/nrgastro.2016.98.
[15] JUNEAU R A,STEVENS J S,APICELLA M A,et al.A thermonuclease of Neisseria gonorrhoeae enhances bacterial escape from killing by neutrophil extracellular traps [J].J Infect Dis,2015,212(2):316-324.DOI:10.1093/infdis/jiv031.
[16] KONSTANTINIDIS T,KAMBAS K,MITSIOS A,et al.Immunomodulatory role of clarithromycin in acinetobacter baumannii infection via formation of neutrophil extracellular traps [J].Antimicrob Agents Chemother,2015,60(2):1040-1048.DOI:10.1128/AAC.02063-15.
[17] MARIN-ESTEBAN V,TURBICA I,DUFOUR G,et al.Afa/Dr diffusely adhering Escherichia coli strain C1845 induces neutrophil extracellular traps that kill bacteria and damage human enterocyte-like cells [J].Infect Immun,2012,80(5):1891-1899.DOI:10.1128/IAI.00050-12.
[18] CRANE J K,BROOME J E,LIS A.Biological activities of uric acid in infection due to enteropathogenic and shiga-toxigenic escherichia coli [J].Infect Immun,2016,84(4):976-988.DOI:10.1128/IAI.01389-15.
[19] BERENDS E T,HORSWILL A R,HASTE N M,et al.Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps [J].J Innate Immun,2010,2(6):576-586.DOI:10.1159/000319909.
[20] LIECHTI G W,GOLDBERG J B.Helicobacter pylori salvages purines from extracellular host cell DNA utilizing the outer membrane-associated nuclease NucT [J].J Bacteriol,2013,195(19):4387-4398.DOI:10.1128/JB.00388-13.
[21] SCHILCHER K,ANDREONI F,UCHIYAMA S,et al.Increased neutrophil extracellular trap-mediated Staphylococcus aureus clearance through inhibition of nuclease activity by clindamycin and immunoglobulin [J].J Infect Dis,2014,210(3):473-482.DOI:10.1093/infdis/jiu091.
[22] HU Z,MURAKAMI T,TAMURA H,et al.Neutrophil extracellular traps induce IL-1β production by macrophages in combination with lipopolysaccharide [J].Int J Mol Med,2017,39(3):549-558.DOI:10.3892/ijmm.2017.2870.
[23] SAHA P,YEOH B S,OLVERA R A,et al.Bacterial siderophores hijack neutrophil functions [J].J Immunol,2017,198(11):4293-4303.DOI:10.4049/jimmunol.1700261.
[24] HALVERSON T W,WILTON M,POON K K,et al.DNA is an antimicrobial component of neutrophil extracellular traps [J].PLoS Pathog,2015,11(1):e1004593.DOI:10.1371/journal.ppat.1004593.
[25] KUBES P,MEHAL W Z.Sterile inflammation in the liver [J].Gastroenterology,2012,143(5):1158-1172.DOI:10.1053/j.gastro.2012.09.008.
[26] MARQUES P E,OLIVEIRA A G,PEREIRA R V,et al.Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice [J].Hepatology,2015,61(1):348-360.DOI:10.1002/hep.27216.
[27] LOWE P P,GYONGYOSI B,SATISHCHANDRAN A,et al.Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration,inflammation and steatosis in early alcoholic hepatitis in mice [J].PLoS One,2017,12(3):e0174544.DOI:10.1371/journal.pone.0174544.
[28] RENSEN S S,BIEGHS V,XANTHOULEA S,et al.Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice [J].PLoS One,2012,7(12):e52411.DOI:10.1371/journal.pone.0052411.
[29] MANSUY-AUBERT V,ZHOU Q L,XIE X,et al.Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity,inflammation,and energy expenditure [J].Cell Metab,2013,17(4):534-548.DOI:10.1016/j.cmet.2013.03.005.
[30] MANO Y,SHIRABE K,YAMASHITA Y,et al.Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma:a retrospective analysis [J].Ann Surg,2013,258(2):301-305.DOI:10.1097/SLA.0b013e318297ad6b.
[31] ASAOKA T,MIYAMOTO A,MAEDA S,et al.Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer [J].Pancreatology,2016,16(3):434-440.DOI:10.1016/j.pan.2015.10.006.
[32] MALIK H Z,PRASAD K R,HALAZUN K J,et al.Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases [J].Ann Surg,2007,246(5):806-814.DOI:10.1097/SLA.0b013e318142d964.
[33] FRIDLENDER Z G,SUN J,KIM S,et al.Polarization of tumor-associated neutrophil phenotype by TGF-beta:“N1” versus “N2” TAN [J].Cancer Cell,2009,16(3):183-194.DOI:10.1016/j.ccr.2009.06.017.
[34] FRIDLENDER Z G,ALBELDA S M.Tumor-associated neutrophils:friend or foe?[J].Carcinogenesis,2012,33(5):949-955.DOI:10.1093/carcin/bgs123.
[35] MILLRUD C R,K?GEDAL ?,KUMLIEN GEORéN S,et al.NET-producing CD16high CD62Ldim neutrophils migrate to tumor sites and predict improved survival in patients with HNSCC [J].Int J Cancer,2017,140(11):2557-2567.DOI:10.1002/ijc.30671.
[36] TOHME S,YAZADANI H O,AL-KHAFAJI A B,et al.Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress [J].Cancer Res,2016,76(6):1367-1380.DOI:10.1158/0008-5472.CAN-15-1591.
[37] PIETERSE E,ROTHER N,GARSEN M,et al.Neutrophil extracellular traps drive endothelial-to-mesenchymal transition [J].Arterioscler Thromb Vasc Biol,2017,37(7):1371-1379.DOI:10.1161/ATVBAHA.117.309002.
[38] NAJMEH S,COOLS-LARTIGUE J,RAYES R F,et al.Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions [J].Int J Cancer,2017,140(10):2321-2330.DOI:10.1002/ijc.30635.
[39] PARK J,WYSOCKI R W,AMOOZGAR Z,et al.Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps [J].Sci Transl Med,2016,8(361):361ra138.DOI:10.1126/scitranslmed.aag1711.
[40] GUGLIETTA S,RESCIGNO M.Hypercoagulation and complement:Connected players in tumor development and metastases [J].Semin Immunol,2016,28(6):578-586.DOI:10.1016/j.smim.2016.10.011.
[41] BOONE B A,ORLICHENKO L,SCHAPIRO N E,et al.The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer [J].Cancer Gene Ther,2015,22(6):326-334.DOI:10.1038/cgt.2015.21.
[42] YANG C,SUN W,CUI W,et al.Procoagulant role of neutrophil extracellular traps in patients with gastric cancer [J].Int J Clin Exp Pathol,2015,8(11):14075-14086.
[43] ARELAKI S,ARAMPATZIOGLOU A,KAMBAS K,et al.Gradient infiltration of neutrophil extracellular traps in colon cancer and evidence for their involvement in tumour growth [J].PLoS One,2016,11(5):e0154484.DOI:10.1371/journal.pone.0154484.
[44] HWANG W L,LAN H Y,CHENG W C,et al.Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer [J].J Hematol Oncol,2019,12(1):10.DOI:10.1186/s13045-019-0699-4.
[45] ABDOL RAZAK N,ELASKALANI O,METHAROM P.Pancreatic cancer-induced neutrophil extracellular traps:a potential contributor to cancer-associated thrombosis [J].Int J Mol Sci,2017,18(3).pii:E487.DOI:10.3390/ijms18030487.
[46] HOSSEINZADEH A,THOMPSON P R,SEGAL B H,et al.Nicotine induces neutrophil extracellular traps [J].J Leukoc Biol,2016,100(5):1105-1112.DOI:10.1189/jlb.3AB0815-379RR.