山东大学耳鼻喉眼学报 ›› 2024, Vol. 38 ›› Issue (2): 163-168.doi: 10.6040/j.issn.1673-3770.0.2023.333

• 综述 • 上一篇    

TLR4/NF-κB通道在糖尿病视网膜病变中的作用

伦英俊1,陈晨2,高宏程2,范清琳3,邰仁清1   

  1. 山东省医学科学院)研究生处, 山东 泰安 271000
  • 出版日期:2024-03-20 发布日期:2024-03-29
  • 通讯作者: 陈晨. E-mail:sdchenchen@126.com

Role of Toll-like receptor 4/nuclear transcription factor-κB channels in diabetic retinopathy

LUN Yingjun1, CHEN Chen2, GAO Hongcheng2, FAN Qinglin3, TAI Renqing1   

  1. 1. Department of Clinical Medical College, Weifang Medical College, Weifang 261000, Shandong, China2. Department of Ophthalmology, Linyi People's Hospital, Linyi 276000, Shandong, China3. Department of Postgraduate, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, Shandong, China
  • Online:2024-03-20 Published:2024-03-29

摘要: 糖尿病视网膜病变(diabetic retinopathy, DR)是一种由糖尿病引起的微血管并发症,也是导致患者失明的首要原因。其发病机制受多种因素影响,例如免疫炎症、氧化应激、多元醇途径等。目前认为免疫炎症机制在DR的发生发展起重要作用。Toll样受体4(Toll-like receptor 4, TLR4)/核转录因子-κB(nuclear factor kappa B, NF-κB)通路是介导炎症因子释放的重要途径,在免疫炎性机制中发挥关键作用。目前不少研究证实抑制TLR4/NF-κB信号通路可有效减轻DR。本文就TLR4/NF-κB通道在DR中的作用进行综述,可为治疗DR提供新的靶点。

关键词: 糖尿病视网膜病变, Toll样受体4, 核转录因子κB, 小胶质细胞, 炎症

Abstract: Diabetic retinopathy(DR)is a microvascular complication caused by diabetes mellitus and is the primary cause of blindness in patients. Its pathogenesis is influenced by various factors,such as immune inflammation, oxidative stress, and polyol pathways. Currently, immune-inflammatory responses are considered to play important roles in the development of DR. The Toll-like receptor 4(TLR4)/nuclear transcription factor-κB(NF-κB)pathway mediates the release of inflammatory factors and plays a key role in inflammatory mechanisms. Several studies have demonstrated that inhibition of the TLR4/NF-κB signaling pathway can effectively treat DR.This review addresses the role of TLR4/NF-κB channels in DR, which may provide novel treatment targets for this disease.

Key words: Diabetic retinopathy, Toll-like receptor 4, Nuclear factor kappa B, Microglia, Inflammation

中图分类号: 

  • R774.1
[1] Tan TE, Wong TY. Diabetic retinopathy: Looking forward to 2030[J]. Front Endocrinol(Lausanne), 2023,13: 1077669. doi:10.3389/fendo.2022.1077669
[2] Teo ZL, Tham YC, Yu M, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis[J]. Ophthalmology, 2021,128(11): 1580-1591. doi:10.1016/j.ophtha.2021.04.027
[3] Yue T, Shi Y, Luo S, et al. The role of inflammation in immune system of diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications[J]. Front Immunol, 2022, 13: 1055087. doi:10.3389/fimmu.2022.1055087
[4] Wallsh JO, Gallemore RP. Anti-VEGF-resistant retinal diseases: a review of the latest treatment options[J]. Cells, 2021,10(5): 1049. doi:10.3390/cells10051049
[5] Taurone S, Ralli M, Nebbioso M, et al. The role of inflammation in diabetic retinopathy: a review[J]. Eur Rev Med Pharmacol Sci, 2020, 24(20): 10319-10329. doi:10.26355/eurrev_202010_23379
[6] Cvitkovic K, Sesar A, Sesar I, et al. Concentrations of selected cytokines and vascular endothelial growth factor in aqueous humor and serum of diabetic patients[J]. Semin Ophthalmol, 2020, 35(2): 126-133. doi:10.1080/08820538.2020.1755320
[7] 王娇娇,李苗,宋宗明. 糖尿病视网膜病变的机制和细胞模型研究进展[J]. 山东大学耳鼻喉眼学报, 2022, 36(5): 93-99. doi:10.6040/j.issn.1673-3770.0.2021.203 WANG Jiaojiao, LI Miao, SONG Zongming. Progress in diabetic retinopathy mechanisms and cellular models[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2022, 36(5): 93-99. doi: 10.6040/j.issn.1673-3770.0.2021.203
[8] Shu X, Hu Y, Huang C, et al. Nimbolide ameliorates the streptozotocin-induced diabetic retinopathy in rats through the inhibition of TLR4/NF-κB signaling pathway[J]. Saudi J Biol Sci, 2021, 28(8): 4255-4262. doi:10.1016/j.sjbs.2021.06.039
[9] Dabi YT, Ajagbe AO, Degechisa ST. Toll-like receptors in pathogenesis of neurodegenerative diseases and their therapeutic potential[J]. Immun Inflamm Dis, 2023, 11(4): e839. doi:10.1002/iid3.839
[10] Balka KR, De Nardo D. Understanding early TLR signaling through the myddosome[J]. J Leukoc Biol, 2019, 105(2): 339-351. doi:10.1002/JLB.MR0318-096R
[11] Romerio A, Peri F. Increasing the chemical variety of small-molecule-based TLR4 modulators: an overview[J]. Front Immunol, 2020, 11: 1210. doi:10.3389/fimmu.2020.01210
[12] Wang L, Wang J, Fang JZ, et al. High glucose induces and activates Toll-like receptor 4 in endothelial cells of diabetic retinopathy[J]. Diabetol Metab Syndr, 2015, 7: 89. doi:10.1186/s13098-015-0086-4
[13] 李晓洁, 许泽鹏, 黄玉婷, 等. Toll样受体4信号通路在糖尿病视网膜病变中的研究进展[J]. 中国中医眼科杂志, 2023, 33(1): 73-79. doi:10.13444/j.cnki.zgzyykzz.2023.01.019 LI Xiaojie, XU Zepeng, HUANG Yuting, et al. Research progress of Toll-like receptor 4 signaling pathway in diabetic retinopathy[J]. China Journal of Chinese Ophthalmology, 2023, 33(1): 73-79. doi:10.13444/j.cnki.zgzyykzz.2023.01.019
[14] Jagtap P, Prasad P, Pateria A, et al. A single step in vitro bioassay mimicking TLR4-LPS pathway and the role of MD2 and CD14 coreceptors[J]. Front Immunol, 2020,11: 5. doi:10.3389/fimmu.2020.00005
[15] Bayer AL, Alcaide P. MyD88: At the heart of inflammatory signaling and cardiovascular disease[J]. J Mol Cell Cardiol, 2021,161: 75-85. doi:10.1016/j.yjmcc.2021.08.001
[16] Fitzgerald KA, Kagan JC. Toll-like receptors and the control of Immunity[J]. Cell, 2020,180(6): 1044-1066. doi:10.1016/j.cell.2020.02.041
[17] Bayan N, Yazdanpanah N, Rezaei N. Role of toll-like receptor 4 in diabetic retinopathy[J]. Pharmacol Res, 2022, 175: 105960. doi:10.1016/j.phrs.2021.105960
[18] Durand JK, Baldwin AS. Targeting IKK and NF-κB for therapy[J]. Adv Protein Chem Struct Biol, 2017, 107: 77-115. doi:10.1016/bs.apcsb.2016.11.006
[19] Zhang Y, Li H, Wang C, et al. Toll like receptor 4 gene Asp299Gly polymorphism increases the risk of diabetic microvascular complications: a meta analysis[J]. Diabetol Metab Syndr, 2022, 14(1): 79. doi:10.1186/s13098-022-00849-2
[20] Fu H, Liu H. Deletion of toll-like receptor 4 ameliorates diabetic retinopathy in mice[J]. Arch Physiol Biochem,2023, 129(2): 519-525. doi:10.1080/13813455.2020.1841795
[21] Chen H, Yan T, Song Z, et al. MD2 blockade prevents modified LDL-induced retinal injury in diabetes by suppressing NADPH oxidase-4 interaction with Toll-like receptor-4[J]. Exp Mol Med, 2021, 53(4): 681-694. doi:10.1038/s12276-021-00607-w
[22] Mesquida M, Drawnel F, Lait PJ, et al. Modelling macular edema: the effect of IL-6 and IL-6R blockade on human blood-retinal barrier integrity in vitro[J]. Transl Vis Sci Technol,2019, 8(5): 32. doi:10.1167/tvst.8.5.32
[23] Taghavi Y, Hassanshahi G, Kounis NG, et al. Monocyte chemoattractant protein-1(MCP-1/CCL2)in diabetic retinopathy: latest evidence and clinical considerations[J]. J Cell Commun Signal, 2019, 13(4): 451-462. doi: 10.1007/s12079-018-00500-8
[24] O'leary F, Campbell M. The blood-retina barrier in health and disease[J]. FEBS J, 2023, 290(4): 878-891. doi:10.1111/febs.16330
[25] Madore C, Yin ZR, Leibowitz J, et al. Microglia, lifestyle stress, and neurodegeneration[J]. Immunity, 2020, 52(2): 222-240. doi:10.1016/j.immuni.2019.12.003
[26] Mcmenamin PG, Saban DR, Dando S J. Immune cells in the retina and choroid: two different tissue environments that require different defenses and surveillance[J]. Prog Retin Eye Res, 2019, 70: 85-98. doi:10.1016/j.preteyeres.2018.12.002
[27] Altmann C, Schmidt MHH. The role of microglia in diabetic retinopathy: inflammation, microvasculature defects and neurodegeneration[J]. Int J Mol Sci, 2018, 19(1): 110. doi:10.3390/ijms19010110
[28] Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states[J]. Br J Pharmacol, 2016, 173(4): 649-665. doi:10.1111/bph.13139
[29] Wang XL, Chen F, Shi H, et al. Oxymatrine inhibits neuroinflammation by regulating M1/M2 polarization in N9 microglia through the TLR4/NF-κB pathway[J]. Int Immunopharmacol, 2021, 100: 108139. doi:10.1016/j.intimp.2021.108139
[30] Fang MY, Wan WC, Li QM, et al. Asiatic acid attenuates diabetic retinopathy through TLR4/MyD88/NF-κB p65 mediated modulation of microglia polarization[J]. Life Sci, 2021, 277: 119567. doi:10.1016/j.lfs.2021.119567
[31] Gu C, Zhang HJ, Zhao SF, et al. Mesenchymal stem cell exosomal miR-146a mediates the regulation of the TLR4/MyD88/NF-κB signaling pathway in inflammation due to diabetic retinopathy[J]. Comput Math Methods Med, 2022: 3864863. doi:10.1155/2022/3864863
[32] Tang L, Zhang C, Lu L, et al. Melatonin maintains inner blood-retinal barrier by regulating microglia via inhibition of PI3K/Akt/Stat3/NF-κB signaling pathways in experimental diabetic retinopathy[J]. Front Immunol, 2022, 13: 831660. doi:10.3389/fimmu.2022.831660
[33] Jo DH, Yun JH, Cho CS, et al. Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood-retinal barrier in diabetic retinopathy[J]. Glia, 2019, 67(2): 321-331. doi:10.1002/glia.23542
[34] Yun JH, Park SW, Kim KJ, et al. Endothelial STAT3 activation increases vascular leakage through downregulating tight junction proteins: implications for diabetic retinopathy[J]. J Cell Physiol,2017, 232(5): 1123-1134. doi:10.1002/jcp.25575
[35] Arrigo A, Aragona E, Bandello F. VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy[J]. Ann Med, 2022, 54(1): 1089-1111. doi:10.1080/07853890.2022.2064541
[36] Friedman M, Azrad-lebovitz T, Morzaev D, et al. Protective effect of TLR4 ablation against corneal neovascularization following chemical burn in a mouse model[J]. Curr Eye Res,2019, 44(5): 505-513. doi:10.1080/02713683.2018.1564833
[37] Chen W, Zhang J, Zhang P, et al. Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy[J]. FASEB J, 2019, 33(3): 3451-3464. doi:10.1096/fj.201801086RR
[38] Gao T, Lin Z, Jin X. Hydrocortisone suppression of the expression of VEGF may relate to toll-like receptor(TLR)2 and 4[J]. Curr Eye Res, 2009, 34(9): 777-784. doi:10.1080/02713680903067919
[39] Xue L, Hu M, Zhu Q, et al. GRg1 inhibits the TLR4/NF-kB signaling pathway by upregulating miR-216a-5p to reduce growth factors and inflammatory cytokines in DR[J]. Mol Biol Rep, 2023, 50(11): 9379-9394. doi:10.1007/s11033-023-08895-3
[40] Kinuthia UM, Wolf A, Langmann T. Microglia and inflammatory responses in diabetic retinopathy[J]. Front Immunol, 2020,11: 564077. doi:10.3389/fimmu.2020.564077
[41] Boeck M, Thien A, Wolf J, et al. Temporospatial distribution and transcriptional profile of retinal microglia in the oxygen-induced retinopathy mouse model[J]. Glia, 2020, 68(9): 1859-1873. doi:10.1002/glia.23810
[42] Soni D, Sagar P, Takkar B. Diabetic retinal neurodegeneration as a form of diabetic retinopathy[J]. Int Ophthalmol, 2021,41(9):3223-3248. doi:10.1007/s10792-021-01864-4
[43] Bikbova G, Oshitari T, Bikbov M. Diabetic neuropathy of the retina and inflammation: perspectives[J]. Int J Mol Sci, 2023, 24(11): 9166. doi:10.3390/ijms24119166
[44] Seidel A, Liu L, Jiang YD, et al. Loss of TLR4 in endothelial cells but not Müller cells protects the diabetic retina[J]. Exp Eye Res, 2021, 206: 108557. doi:10.1016/j.exer.2021.108557
[45] Park HY, Kim JH, Park CK. Neuronal cell death in the inner retina and the influence of vascular endothelial growth factor inhibition in a diabetic rat model[J]. Am J Pathol, 2014, 184(6): 1752-1762. doi:10.1016/j.ajpath.2014.02.016
[46] Ferreira de Melo IM, Martins Ferreira CG, Lima da Silva Souza EH, et al. Melatonin regulates the expression of inflammatory cytokines, VEGF and apoptosis in diabetic retinopathy in rats[J]. Chem Biol Interact, 2020, 327: 109183. doi:10.1016/j.cbi.2020.109183
[47] Araszkiewicz A, Zozulinska-Ziolkiewicz D. Retinal neurodegeneration in the course of diabetes-pathogenesis and clinical perspective[J]. Curr Neuropharmacol, 2016, 14(8): 805-809. doi:10.2174/1570159x14666160225154536
[48] Pereiro X, Ruzafa N, Acera A, et al. Dexamethasone protects retinal ganglion cells but not Müller glia against hyperglycemia in vitro[J]. PLoS One, 2018, 13(11): e0207913. doi:10.1371/journal.pone.0207913
[49] Zhao M, Li CH, Liu YL. Toll-like receptor(TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications[J]. Genet Mol Res, 2016, 15(2): 10. doi:10.4238/gmr.15026998
[50] Nakano Y, Shimazawa M, Ojino K, et al. Toll-like receptor 4 inhibitor protects against retinal ganglion cell damage induced by optic nerve crush in mice[J]. J Pharmacol Sci. 2017, 133(3): 176-183. doi:10.1016/j.jphs.2017.02.012
[51] Liu L, Jiang YD, Steinle J. Epac1 regulates TLR4 signaling in the diabetic retinal vasculature[J]. Cytokine, 2021, 144: 155576. doi:10.1016/j.cyto.2021.155576
[1] 李凯,罗丹. 润目灵方激活LC3-ATG5自噬通路抑制炎症因子表达改善干眼大鼠眼表损伤的机制[J]. 山东大学耳鼻喉眼学报, 2026, 40(3): 92-101.
[2] 赵娟,焦万珍,赵博军. UWFSS-OCTA检测糖尿病视网膜病变微循环的变化[J]. 山东大学耳鼻喉眼学报, 2026, 40(2): 80-86.
[3] 辛敏,王少明. 炎症与感染性嗅觉功能障碍的神经免疫机制及治疗策略[J]. 山东大学耳鼻喉眼学报, 2026, 40(2): 111-124.
[4] 孙庆祝,沈健,陈星,吴雁冰,曾论. 代谢指标在预测糖尿病性黄斑水肿患者雷珠单抗疗效中的作用[J]. 山东大学耳鼻喉眼学报, 2026, 40(1): 74-81.
[5] 段思妤,薛金梅. 组蛋白去乙酰化酶2在慢性气道炎症性疾病糖皮质激素抵抗中的研究进展[J]. 山东大学耳鼻喉眼学报, 2026, 40(1): 120-126.
[6] 李莉琳,李馨仪,关建. 阻塞性睡眠呼吸暂停与抑郁症共病机制的研究进展[J]. 山东大学耳鼻喉眼学报, 2025, 39(3): 89-96.
[7] 毛一恒,冯洁,何润田. 高血脂对视网膜损害与脉络膜厚度关系研究[J]. 山东大学耳鼻喉眼学报, 2025, 39(3): 162-167.
[8] 王文晴,张丹,朱梦迪,王路阳,杨培培,孙思思,张秋敏,周慧. 慢性鼻窦炎伴鼻息肉复发手术时临床及组织病理学特征变化[J]. 山东大学耳鼻喉眼学报, 2025, 39(1): 46-53.
[9] 张婕,尼玛吉宗,徐小东,周菁,刘建敏,罗依蕤,杜进涛,巴罗. 藏红花素在嗜酸性慢性鼻窦炎伴鼻息肉中调控2型炎症反应的研究[J]. 山东大学耳鼻喉眼学报, 2025, 39(1): 61-67.
[10] 王曼娴,郑泉,杨亮. 细菌裂解物治疗变应性鼻炎的研究进展[J]. 山东大学耳鼻喉眼学报, 2025, 39(1): 141-145.
[11] 辛梦,纪芳,代春华,张靖,刘澍. 医用透明质酸钠与平衡盐溶液在微创玻璃体手术中对眼表保护的影响[J]. 山东大学耳鼻喉眼学报, 2024, 38(5): 58-65.
[12] 张静祎,董湘依,牟亚魁,宋西成. 细胞焦亡在耳鼻咽喉科疾病中的研究进展[J]. 山东大学耳鼻喉眼学报, 2024, 38(4): 140-148.
[13] 张丽净,冯晓星,刘南仙,赵辉明,陈月华. 石墨烯养护鼻罩结合尘螨的皮下特异性免疫治疗在尘螨变应性鼻炎患者中的应用分析[J]. 山东大学耳鼻喉眼学报, 2024, 38(3): 26-32.
[14] 常威威,焦万珍,崔艳艳,赵杰,刘兆强,赵博军. 糖尿病性黄斑缺血的研究进展[J]. 山东大学耳鼻喉眼学报, 2024, 38(3): 130-136.
[15] 叶强,洛松巴宗,南苏亭,王浩,马进海,律鹏,张文芳. 色素上皮衍生因子与干眼的研究进展[J]. 山东大学耳鼻喉眼学报, 2024, 38(3): 151-156.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!