基于肠道紧密连接的细胞旁通透性研究进展

doi:10.16431/j.cnki.1671-7236.2024.12.009

摘要/Abstract

摘要： 肠上皮细胞紧密连接作为肠道屏障的重要组成部分，不仅决定肠道的细胞旁通透性，还在维护肠道内环境稳定、防止有害物质侵入等方面发挥重要作用。当紧密连接的结构或功能受损时，肠道屏障的完整性遭到破坏，导致细胞旁通透性显著增加，细菌、内毒素、病毒及大分子物质便可通过细胞旁路途径进入组织和器官，从而引起肠道疾病发生。但是不同分子通过肠道紧密连接的途径也不同，目前证明主要有两种细胞旁路途径，即孔隙途径和渗漏途径。这两种途径在分子大小、通透性及调控机制方面有所不同，孔隙途径主要涉及小分子物质通过，通过调节紧密连接蛋白Claudin-2的表达影响孔隙途径通透性，进而影响肠道屏障功能；而渗漏途径主要涉及大分子物质通过，Occludin、Tricellulin、ZO-1等紧密连接蛋白在这一途径中发挥关键作用，以维护肠道屏障的完整性。笔者以影响孔隙途径和渗漏途径通透性的相关蛋白为出发点，阐明这些蛋白影响孔隙途径和渗漏途径通透性的调控机制，从而防止有毒有害物质进入体内，以期为肠上皮紧密连接屏障破坏引起肠道疾病的防治提供理论依据。

关键词: 紧密连接屏障; 孔隙途径; 渗漏途径

Abstract: As an important component of the intestinal barrier,the intestinal epithelial cell tight junction not only determines the paracellular permeability of the intestinal tract,but also plays an important role in maintaining the stability of the intestinal environment and preventing the invasion of harmful substances.When the structure or function of the tight junctions is damaged,the integrity of the intestinal barrier is disrupted,resulting in a significant increase in paracellular permeability,bacteria,endotoxins,viruses and macromolecules can enter tissues and organs through the paracellular pathway,leading to the occurrence of intestinal diseases.However,different molecules have different ways to pass through the intestinal tight junctions,and there are two primary paracellular pathways,the pore pathway and the leak pathway.These two pathways are different in terms of molecular size,permeability and regulatory mechanisms.The pore pathway mainly involves the passage of small molecules,and regulating the expression of tight junction protein Claudin-2 affects the permeability of the pore pathway,which in turn affects the function of the intestinal barrier. Whereas the leak pathway mainly involves the passage of large molecules,and tight junction proteins,such as Occludin,Tricellulin and ZO-1,play a key role in this pathway.Occludin,Tricellulin,ZO-1 and other tight junction proteins play a key role in this pathway to maintain the integrity of the intestinal barrier.Taking the relevant proteins affecting the permeability of the pore pathway and the leak pathway as the starting point,the author elucidated the regulatory mechanisms of these proteins affecting the permeability of the pore pathway and the leak pathway,thus preventing the entry of toxic and harmful substances into the body,with a view to provide theoretical basis for the prevention and treatment of intestinal diseases caused by the disruption of the intestinal epithelial tight junction barrier.

Key words: tight junction barrier; pore pathway; leak pathway

中图分类号:

S852.21

李明, 孙娟, 王曼茜, 李庆豪, 李艺雷, 马俊兴, 金鑫. 基于肠道紧密连接的细胞旁通透性研究进展[J]. 中国畜牧兽医, 2024, 51(12): 5209-5217.

LI Ming, SUN Juan, WANG Manxi, LI Qinghao, LI Yilei, MA Junxing, JIN Xin. Advances on Paracellular Permeability Based on Intestinal Tight Junctions[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(12): 5209-5217.

参考文献

[1] MCGUINNESS S, SAJJADI S, WEBER C R, et al.Computational models of Claudin assembly in tight junctions and strand properties[J].International Journal of Molecular Sciences, 2024, 25(6):3364.
[2] 杨靖源, 蒙俊, 杨堃.肠紧密连接蛋白与肠道屏障功能[J].医学综述, 2022, 28(2):235-239.YANG J Y, MENG J, YANG K.Intestinal tight junction protein and intestinal barrier function[J].Medical Review, 2022, 28(2):235-239.(in Chinese)
[3] NYIMANU D, BEHM C, CHOUDHURY S, et al.The role of Claudin-2 in kedney function and dysfunction[J].Biochemical Society Transactions, 2023, 51(4):1437-1445.
[4] NEYRINCK-LEGLANTIER D, LESAGE J, BLACHER S, et al.ZO-1 intracellular localization organizes immune response in non-small cell lung cancer[J].Frontiers in Cell and Developmental Biology, 2021, 9:749364.
[5] SCHOSSLEITNER K, RAUSCHER S, GRÖGER M, et al.Evidence that Cingulin regulates endothelial barrier function in vitro and in vivo[J].Arteriosclerosis, Thrombosis, and Vascular Biology, 2016, 36(4):647-654.
[6] KUO W T, ODENWALD M A, TURNER J R, et al.Tight junction proteins Occludin and ZO-1 as regulators of epithelial proliferation and survival[J].Annals of the New York Academy of Sciences, 2022, 1514(1):21-33.
[7] FUJIWARA S, NGUYEN T P, FURUSE K, et al.Tight junction formation by a Claudin mutant lacking the COOH-terminal PDZ domain-binding motif[J].Annals of the New York Academy of Sciences, 2022, 1516(1):85-94.
[8] CURRY J N, TOKUDA S, MCANULTY P, et al.Combinatorial expression of claudins in the proximal renal tubule and its functional consequences[J].American Journal of Physiology-Renal Physiology, 2020, 318(5):F1138-F1146.
[9] BERSELLI A, ALBERINI G, BENFENATI F, et al.The impact of pathogenic and artificial mutations on Claudin-5 selectivity from molecular dynamics simulations[J].Computational and Structural Biotechnology, 2023, 21:2640-2653.
[10] THENET S, CARRIÈRE V.Special issue on the "Regulation and physiopathology of the gut barrier"[J].International Journal of Molecular Sciences, 2022, 23(18):10638.
[11] ROSENTHAL R, GVNZEL D, PIONTEK J, et al.Claudin-15 forms a water channel through the tight junction with distinct function compared to claudin-2[J].Acta Physiologica, 2020, 228(1):e13334.
[12] MOONWIRIVAKIT A, PATHOMTHONGTAWEECHAI N, STEINHAGEN P R, et al.Tight junctions:From molecules to gastrointestinal diseases[J].Tissue Barriers, 2023, 11(2):2077620.
[13] MONACO A, OVRYN B, AXIS J, et al.The epithelial cell leak pathway[J].International Journal of Molecular Sciences, 2021, 22(14):7677.
[14] CHO Y, HARAGUCHI D, SHIGETOMI K, et al.Tricellulin secures the epithelial barrier at tricellular junctions by interacting with actomyosin[J].The Journal of Cell Biology, 2022, 221(4):e202009037.
[15] TANG Z, YANG Y, YANG M, et al.Elucidating the modulatory role of dietary hydroxyproline on the integrity and functional performance of the intestinal barrier in early-weaned piglets:A comprehensive analysis of its interplay with the gut microbiota and metabolites[J].International Immunopharmacology, 2024, 134:112268.
[16] LI Y, CHEN T, CHEN L, et al.Construction of hyaluronic acid-functionalized magnolol nanoparticles for ulcerative colitis treatment[J]. International Journal of Biological Macromolecules, 2024, 268(P2):131920.
[17] MEOLI L, GVNZEL D.Channel functions of Claudins in the organization of biological systems[J].Biomembranes, 2020, 1862(9):183344.
[18] PLAZA J, MIZGUZE A, BASTIDA G, et al.Genetic variants associated with biological treatment response in inflammatory bowel disease:A systematic review[J].International Journal of Molecular Sciences, 2024, 25(7):3717.
[19] SCHUMANN M, GVNZEL D, BUERGEL N, et al.Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease[J].Gut, 2012, 61(2):220-228.
[20] CHEN Q, ZHANG H, SUN C Y, et al.Evaluation of two laboratory model methods for diarrheal irritable bowel syndrome[J].Molecular Medicine, 2023, 29(1):5.
[21] KRUG S M, GRVNHAGEN C, ALLERS K, et al.Macromolecule translocation across the intestinal mucosa of HIV-infected patients by transcytosis and through apoptotic leaks[J].Cells, 2023, 12(14):1887.
[22] BARRETT K E.Claudin-2 pore causes leak that breaches the dam in intestinal inflammation[J].The Journal of Clinical Investigation, 2020, 130(10):5100-5101.
[23] ZHANG X, ZHANG Y, HE Y, et al.β-glucan protects against necrotizing enterocolitis in mice by inhibiting intestinal inflammation, improving the gut barrier, and modulating gut microbiota[J].Jouranl of Translational Medicine, 2023, 21(1):14.
[24] EPPLE H J, FRIEBEL J, MOOS V, et al.Architectural and functional alterations of the small intestinal mucosa in classical Whipple’s disease[J].Mucosal Immunology, 2017, 10(6):1542-1552.
[25] KOZIEł M J, ZIAJA M, PIASTOWSKA-CIESIELSKA A W.Intestinal barrier, Claudins and Mycotoxins[J].Toxins, 2021, 13(11):758.
[26] ZHANG C, YAN J, XIAO Y, et al.Inhibition of autophagic degradation process contributes to Claudin-2 expression increase and epithelial tight junction dysfunction in TNF-α treated cell monolayers[J].International Journal of Molecular Sciences, 2017, 18(1):157.
[27] MEYER F, WENDLING D, DEMOUGEOT C, et al.Cytokines and intestinal epithelial permeability:A systematic review[J].Autoimmunity Reviews, 2023, 22(6):103331.
[28] HUANG X, OSHIMA T, TOMITA T, et al.Butyrate alleviates cytokine-induced barrier dysfunction by modifying Claudin-2 levels[J].Biology, 2021, 10(3):205.
[29] JIN X, YOU L, QIAO J, et al.Autophagy in colitis-associated colon cancer:Exploring its potential role in reducing initiation and preventing IBD-related CAC development[J].Autophagy, 2024, 20(2):242-258.
[30] 冯燕海, 王凤君.紧密连接蛋白Claudin-2研究进展[J].重庆医学, 2018, 47(5):697-699.FENG Y H, WANG F J.Research progress on Claudin-2 tight junction protein[J].Chongqing Medicine, 2018, 47(5):697-699.(in Chinese)
[31] TSAI P Y, ZHANG B, HE W Q, et al.IL-22 upregulates epithelial Claudin-2 to drive diarrhea and enteric pathogen clearance[J].Cell Host and Microbe, 2017, 21(6):671-681.
[32] BOSMAN E S, CHAN J M, BHULLAR K, et al.Investigation of host and pathogen contributions to infectious colitis using the Citrobacter rodentium mouse model of infection[J].Methods in Molecular Biology, 2016, 1422:225-241.
[33] SASSI A, WANG Y, CHASSOT A, et al.Interaction between epithelial sodium channel γ-subunit and Claudin-8 modulates paracellular sodium permeability in renal collecting duct[J].Journal of the American Society of Nephrology, 2020, 31(5):1009-1023.
[34] AHMAD R, CHATURVEDI R, OLIVARES-VILLAGÓMEZ D, et al.Targeted colonic Claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis[J].Mucosal Immunology, 2014, 7(6):1340-1353.
[35] SEO K, SEO J, YEUN J, et al.The role of mucosal barriers in human gut health[J].Archives of Pharmacal Research, 2021, 44(4):325-341.
[36] CAPALDA C T.Claudin barriers on the brink:How conflicting tissue and cellular priorities drive IBD pathogenesis[J].International Journal of Molecular Sciences, 2023, 24(10):8562.
[37] BUHRMANN C, SHAYAN P, KRAEHE P, et al.Resveratrol induces chemosensitization to 5-fluorouracil through up-regulation of intercellular junctions, epithelial-to-mesenchymal transition and apoptosis in colorectal cancer[J].Biochemical Pharmacology, 2015, 98(1):51-68.
[38] WEI M, ZHANG Y, YANG X, et al.Claudin-2 promotes colorectal cancer growth and metastasis by suppressing NDRG1 transcription[J].Clinical and Translational Medicine, 2021, 11(12):e667.
[39] OAMI T, ABTAHI S, SHIMAZUI T, et al.Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis[J].Proceedings of the National Academy of Sciences of the United States of America, 2024, 121(10):e2217877121.
[40] AYALA-TORRES C, KRUG S M, ROSENTHAL R, et al.Angulin-1(LSR) affects paracellular water transport, however only in tight epithelial cells[J].International Journal of Molecular Sciences, 2021, 22(15):7827.
[41] ZHU L, HAN J, LI L, et al.Claudin family participates in the pathogenesis of inflammatory bowel diseases and colitis-associated colorectal cancer[J].Frontiers in Immunology, 2019, 10:1441.
[42] SHIGETOMI K, ONO Y, MATSUZAWA K, et al.Cholesterol-rich domain formation mediated by ZO proteins is essential for tight junction formation[J].Proceedings of the National Academy of Sciences of the United States of America, 2023, 120(8):e2217561120.
[43] RALEIGH D R, BOE D M, YU D, et al.Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function[J].The Journal of Cell Biology, 2011, 193(3):565-582.
[44] MARCHELLETTA R R, KRISHNAN M, SPALINGER R M, et al.T cell protein tyrosine phosphatase protects intestinal barrier function by restricting epithelial tight junction remodeling[J]. Journal of Clinical Investigation, 2021, 131(17):e138230.
[45] WANG L, SONG X, ZHOU Y, et al.Sclareol protected against intestinal barrier dysfunction ameliorating Crohn’s disease-like colitis via Nrf2/NF-B/MLCK signalling[J].International Immunopharmacology, 2024, 133:112140.
[46] SU L, NALLE S C, SHEN L, et al.TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis[J].Gastroenterology, 2013, 145(2):407-415.
[47] WEBER C R, RALEIGH D R, SU L, et al.Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity[J].The Journal of Biological Chemistry, 2010, 285(16):12037-12046.
[48] ZHENG S, WANG Z, CAO X, et al.Insights into the effects of chronic combined chromium-nickel exposure on colon damage in mice through transcriptomic analysis and in vitro gastrointestinal digestion assay[J].Ecotoxicology and Environmental Safety, 2024, 279:116458.
[49] XU D, LIU D, JIANG N, et al.Narirutin mitigates dextrose sodium sulfate-induced colitis in mice by modulating intestinal flora[J].Phytomedicine, 2024, 130:155730.
[50] SUGIYAMA S, SASAKI T, TANAKA H, et al.The tight junction protein Occludin modulates blood-brain barrier integrity and neurological function after ischemic stroke in mice[J].Scientific Reports, 2023, 13(1):2892.
[51] GRAHAM W V, HE W, MARCHIANDO A M, et al.Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis[J].Nature Medicine, 2019, 25(4):690-700.
[52] JIN Y, BLIKSLAGER A T.Myosin light chain kinase mediates intestinal barrier dysfunction via Occludin endocytosis during anoxia/reoxygenation injury[J].American Journal of Physiology. Cell Physiology, 2016, 311(6):C996-C1004.
[53] SAHA K, SUBRAMENIUM G A, WANG A, et al.Autophagy reduces the degradation and promotes membrane localization of Occludin to enhance the intestinal epithelial tight junction barrier against paracellular macromolecule flux[J].Journal of Crohn^,s and Colities, 2023, 17(3):433-449.
[54] MARCHIANDO A M, SHEN L, GRAHAM W V, et al.Caveolin-1-dependent Occludin endocytosis is required for TNF-induced tight junction regulation in vivo[J].The Journal of Cell Biology, 2010, 189(1):111-126.
[55] ARASH A, PEYMAN A, JOHAN G, et al.Epithelial integrity, junctional complexes, and biomarkers associated with intestinal functions[J].Tissue Barriers, 2021, 10(3):1996830.
[56] MIN S N, CONG X, ZHANG Y, et al.Tricellulin modulates transport of macromolecules in the salivary gland[J].Journal of Dental Research, 2020, 99(3):302-310.
[57] 毛祥娣, 杨泽希, 丛馨, 等.三细胞紧密连接蛋白tricellulin表达与功能调控的研究进展[J].中国病理生理杂志, 2020, 36(12):2276-2282.MAO X D, YANG Z X, CONG X, et al.Progress in expression and functional of tricellular tight junction protein tricellulin[J].Chinese Journal of Pathophysiology, 2020, 36(12):2276-2282.(in Chinese)
[58] SAITO A C, HIGASHI T, FUKAZAWA Y, et al.Occludin and Tricellulin facilitate formation of anastomosing tight-junction strand network to improve barrier function[J].Molecular Biology of the Cell, 2021, 32(8):722-738.
[59] HAAS A J, ZIHNI C, KRUG S M, et al.ZO-1 guides tight junction assembly and epithelial morphogenesis via cytoskeletal tension-dependent and -independent functions[J].Cells, 2022, 11(23):3775.
[60] DING S, LI K, HAN X, et al.Long-term use of etomidate disrupts the intestinal homeostasis and nervous system in mice[J].Toxicology, 2024, 504:153802.
[61] SAITO A C, ENDO C, FUKAZAWA Y, et al.Effects of TAMP family on the tight junction strand network and barrier function in epithelial cells[J].Annals of the New York Academy Sciences, 2022, 1517(1):234-250.
[62] VAN ITALLIE C M, TIETGENS A J, ANDERSON J M.Visualizing the dynamic coupling of claudin strands to the actin cytoskeleton through ZO-1[J].Molecular Biology of the Cell, 2017, 28(4):524-534.
[63] YU S, HE J, XIE K.Zonula Occludens proteins signaling in inflammation and tumorigenesis[J].International Journal of Biological Sciences, 2023, 19(12):3804-3815.
[64] TOKUDA S, HIGASHI T, FURUSE M.ZO-1 knockout by TALEN-mediated gene targeting in MDCK cells: Involvement of ZO-1 in the regulation of cytoskeleton and cell shape[J].PLoS One, 2014, 9(8):e104994.
[65] RODGERS L S, BEAM M T, ANDERSON J M, et al.Epithelial barrier assembly requires coordinated activity of multiple domains of the tight junction protein ZO-1[J].The Journal of Cell Sciences, 2013, 126(Pt 7):1565-1575.
[66] SPADARO D, LE S, LAROCHE T, et al.Tension-dependent stretching activates ZO-1 to control the junctional localization of its interactors[J].Current Biology, 2017, 27(24):3783-3795.e8.
[67] ODENWALD M A, CHOI W, KUO W T, et al.The scaffolding protein ZO-1 coordinates actomyosin and epithelial apical specializations in vitro and in vivo[J].The Journal of Biological Chemistry, 2018, 293(45):17317-17335.