Research progress of neutrophil extracel lulartrapsin retinal neovascular diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Yaling ¹ , Tang Jiannan ² , Cui Kaixuan ¹ , Liu Ping ¹ , Wei Peiling ¹ ,  Zhang Guoming ¹

1. Shenzhen Eye Hospital, Southern Medical University, Shenzhen 518040, China;
2. Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Shenzhen 518040, China Correspondingauthor: ZhangGuoming, Email: zhang-guoming@163.com;

Corresponding?author：

Zhang Guoming, Email: zhang-guoming@163.com

Keywords：

Neutrophil extracellular traps; Retinal neovascular diseases; Molecular mechanisms; Review

DOI：

10.3760/cma.j.cn511434-20250915-00399

Video：

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Abstract Full text Figures/Tables Video References Cited by

Neutrophil extracellular traps (NETs), composed of deoxyribonucleic acid (DNA), histones, and granule enzymes, exhibit a “double-edged sword” effect in retinal neovascularization (RNV) diseases. The formation of NETs involves classical lytic and non-lytic pathways, as well as peptidylarginine deiminase 4 (PAD4)-dependent and reactive oxygen species-dependent molecular mechanisms. Across different types of RNV, the roles of NETs vary markedly. In diabetic retinopathy, NETs accelerate disease progression by amplifying inflammatory responses, disrupting the blood-retinal barrier, and increasing vascular permeability. During specific stages of retinopathy of prematurity, NETs participate in the clearance of senescent vessels and promote beneficial vascular remodeling. In retinal vein occlusion, their pro-coagulant and pro-inflammatory properties may exacerbate thrombosis and ischemia. The functions of NETs are dynamically regulated by disease stage, microenvironmental factors, and interactions with immune cells. Therefore, therapeutic strategies aimed at clearing NETs (e.g., deoxyribonuclease I) or inhibiting NET formation (e.g., PAD4 inhibitors) may serve as complementary approaches to current anti-vascular endothelial growth factor therapies, although further studies are needed to elucidate optimal intervention timing, safety, and combination treatment strategies for clinical translation.

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1. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss[J/OL]. Eye Vis (Lond), 2015, 2: 17[2015-09-30]. https://pubmed.ncbi.nlm.nih.gov/26605370/. DOI: 10.1186/s40662-015-0026-2.
2. Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies[J/OL]. JCI Insight, 2017, 2(14): e93751[2017-07-20]. https://pubmed.ncbi.nlm.nih.gov/28724805/. DOI: 10.1172/jci.insight.93751.
3. Hellstr?m A, Smith LE, Dammann O. Retinopathy of prematurity[J]. Lancet, 2013, 382(9902): 1445-1457. DOI: 10.1016/S0140-6736(13)60178-6.
4. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity[J]. N Engl J Med, 2012, 367(26): 2515-2526. DOI: 10.1056/NEJMra1208129.
5. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments[J/OL]. Neuron, 2010, 67(2): 181-198. DOI: 10.1016/j.neuron.2010.07.002.
6. Sapieha P. Eyeing central neurons in vascular growth and reparative angiogenesis[J]. Blood, 2012, 120(11): 2182-2194. DOI: 10.1182/blood-2012-04-396846.
7. Lo EH. A new penumbra: transitioning from injury into repair after stroke[J]. Nat Med, 2008, 14(5): 497-500. DOI: 10.1038/nm1735.
8. Lange CA, Bainbridge JW. Oxygen sensing in retinal health and disease[J]. Ophthalmologica, 2012, 227(3): 115-131. DOI: 10.1159/000331418.
9. Shields JA, Shields CL, Honavar SG, et al. Clinical variations and complications of Coats disease in 150 cases: the 2000 Sanford Gifford Memorial Lecture[J]. Am J Ophthalmol, 2001, 131(5): 561-571. DOI: 10.1016/s0002-9394(00)00883-7.
10. Fielder A, Blencowe H, O'Connor A, et al. Impact of retinopathy of prematurity on ocular structures and visual functions[J]. Arch Dis Child Fetal Neonatal Ed, 2015, 100(2): 179-184. DOI: 10.1136/archdischild-2014-306207.
11. Tsai AS, Chou HD, Ling XC, et al. Assessment and management of retinopathy of prematurity in the era of anti-vascular endothelial growth factor (VEGF)[J/OL]. Prog Retin Eye Res, 2022, 88: 101018[2021-11-09]. https://pubmed.ncbi.nlm.nih.gov/34763060/. DOI: 10.1016/j.preteyeres.2021.101018.
12. 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.
13. Wang H, Kim SJ, Lei Y, et al. Neutrophil extracellular traps in homeostasis and disease[J/OL]. Signal Transduct Target Ther, 2024, 9(1): 235[2024-09-20]. https://pubmed.ncbi.nlm.nih.gov/39300084/. DOI: 10.1038/s41392-024-01933-x.
14. Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps[J]. J Cell Biol, 2007, 176(2): 231-241. DOI: 10.1083/jcb.200606027.
15. Hampton MB, Kettle AJ, Winterbourn CC. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing[J]. Blood, 1998, 92(9): 3007-3017. DOI: 10.1182/blood.V92.9.3007.
16. Rhee SG. Cell signaling. H2O2, a necessary evil for cell signaling[J]. Science, 2006, 312(5782): 1882-1883. DOI: 10.1126/science.1130481.
17. Reth M. Hydrogen peroxide as second messenger in lymphocyte activation[J]. Nat Immunol, 2002, 3(12): 1129-1134. DOI: 10.1038/ni1202-1129.
18. Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease[J]. Curr Opin Immunol, 2003, 15(5): 578-584. DOI: 10.1016/s0952-7915(03)00109-2.
19. Yousefi S, Gold JA, Andina N, et al. , Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense[J]. Nat Med, 2008, 14(9): 949-953. DOI: 10.1038/nm.1855.
20. Pilsczek FH, Salina D, Poon KK, et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus[J]. J Immunol, 2010, 185(12): 7413-7425. DOI: 10.4049/jimmunol.1000675.
21. Clark SR, Ma AC, Tavener SA, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood[J]. Nat Med, 2007, 13(4): 463-469. DOI: 10.1038/nm1565.
22. Yipp BG, Kubes P. NETosis: how vital is it?[J]. Blood, 2013, 122(16): 2784-2794. DOI: 10.1182/blood-2013-04-457671.
23. Wang Y, Li M, Stadler S, et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation[J]. J Cell Biol, 2009, 184(2): 205-213. DOI: 10.1083/jcb.200806072.
24. Neeli I, Khan SN, Radic M. Histone deimination as a response to inflammatory stimuli in neutrophils[J]. J Immunol, 2008, 180(3): 1895-1902. DOI: 10.4049/jimmunol.180.3.1895.
25. Douda DN, Khan MA, Grasemann H, et al. SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx[J]. Proc Natl Acad Sci USA, 2015, 112(9): 2817-2822. DOI: 10.1073/pnas.1414055112.
26. Maga?a-Guerrero FS, Aguayo-Flores JE, Buentello-Volante B, et al. Spontaneous neutrophil extracellular traps release are inflammatory markers associated with hyperglycemia and renal failure on diabetic retinopathy[J/OL]. Biomedicines, 2023, 11(7): 1791[2023-06-22]. https://pubmed.ncbi.nlm.nih.gov/37509431/. DOI: 10.3390/biomedicines11071791.
27. Zeng J, Wu M, Zhou Y, et al. Neutrophil extracellular traps (NETs) in ocular diseases: an update[J/OL]. Biomolecules, 2022, 12(10): 1440[2022-10-08]. https://pubmed.ncbi.nlm.nih.gov/36291649/. DOI: 10.3390/biom12101440.
28. Liu Z, Perry LA, Penny-Dimri JC, et al. The association of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio with retinal vein occlusion: a systematic review and meta-analysis[J/OL]. Acta Ophthalmol, 2022, 100(3): e635-e647[2021-07-04]. https://pubmed.ncbi.nlm.nih.gov/34219390/. DOI: 10.1111/aos.14955.
29. Wan W, Liu H, Long Y, et al. The association between circulating neutrophil extracellular trap related biomarkers and retinal vein occlusion incidence: a case-control pilot study[J/OL]. Exp Eye Res, 2021, 210: 108702[2021-07-13]. https://pubmed.ncbi.nlm.nih.gov/34270977/. DOI: 10.1016/j.exer.2021.108702.
30. Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities[J]. J Clin Invest, 2013, 123(3): 966-972. DOI: 10.1172/JCI64098.
31. Binet F, Cagnone G, Crespo-Garcia S, et al. Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy[J/OL]. Science, 2020, 369(6506): eaay5356[2020-08-21]. https://pubmed.ncbi.nlm.nih.gov/32820093/. DOI: 10.1126/science.aay5356.
32. Zhao B, Zhao Y, Sun X. Mechanism and therapeutic targets of circulating immune cells in diabetic retinopathy[J/OL]. Pharmacol Res, 2024, 210: 107505[2024-11-14]. https://pubmed.ncbi.nlm.nih.gov/39547465/. DOI: 10.1016/j.phrs.2024.107505.
33. Zhu Y, Xia X, He Q, et al. Diabetes-associated neutrophil NETosis: pathogenesis and interventional target of diabetic complications[J/OL]. Front Endocrinol (Lausanne), 2023, 14: 1202463[2023-08-03]. https://pubmed.ncbi.nlm.nih.gov/37600700/. DOI: 10.3389/fendo.2023.1202463.
34. Floyd JL, Prasad R, Dupont MD, et al. Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes[J]. Diabetologia, 2025, 68(4): 866-889. DOI: 10.1007/s00125-024-06349-4.
35. Wang L, Zhou X, Yin Y, et al. Hyperglycemia induces neutrophil extracellular traps formation through an NADPH oxidase-dependent pathway in diabetic retinopathy[J/OL]. Front Immunol, 2019, 9: 3076[2019-01-08]. https://pubmed.ncbi.nlm.nih.gov/30671057/. DOI: 10.3389/fimmu.2018.03076.
36. Sakini ASA, Hamid AK, Alkhuzaie ZA, et al. Diabetic macular edema (DME): dissecting pathogenesis, prognostication, diagnostic modalities along with current and futuristic therapeutic insights[J/OL]. Int J Retina Vitreous, 2024. 10(1): 83[2024-10-28]. https://pubmed.ncbi.nlm.nih.gov/39468614/. DOI: 10.1186/s40942-024-00603-y.
37. Li T, Qian Y, Li H, et al. Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion[J/OL]. Cell Commun Signal, 2024, 22(1): 275[2024-05-16]. https://pubmed.ncbi.nlm.nih.gov/38755602/. DOI: 10.1186/s12964-024-01653-3.
38. Connor KM, Krah NM, Dennison RJ, et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis[J]. Nat Protoc, 2009, 4(11): 1565-1573. DOI: 10.1038/nprot.2009.187.
39. Maurya M, Liu CH, Bora K, et al. Animal models of retinopathy of prematurity: advances and metabolic regulators[J/OL]. Biomedicines, 2024, 12(9): 1937[2024-08-23]. https://pubmed.ncbi.nlm.nih.gov/39335451/. DOI: 10.3390/biomedicines12091937.
40. Tan W, Li B, Wang Z, et al. Novel potential biomarkers for retinopathy of prematurity[J/OL]. Front Med (Lausanne), 2022. 9: 840030[2022-02-02]. https://pubmed.ncbi.nlm.nih.gov/35187013/. DOI: 10.3389/fmed.2022.840030.
41. Jaulim A, Ahmed B, Khanam T, et al. Branch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature[J]. Retina, 2013, 33(5): 901-910. DOI: 10.1097/IAE.0b013e3182870c15.
42. Deng G, Zou X, Liu Z, et al. The protective effect of DNase I in retinal vein occlusion[J]. Biomol Biomed, 2024, 24(2): 387-394. DOI: 10.17305/bb.2023.9780.
43. Mutua V, Gershwin LJ. A Review of Neutrophil extracellular traps (NETs) in disease: potential anti- NETstherapeutics[J]. Clin Rev Allergy Immunol, 2021, 61(2): 194-211. DOI: 10.1007/s12016-020-08804-7.
44. Lood C, Blanco LP, Purmalek MM, 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.
45. Kessenbrock K, Krumbholz M, Schonermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis[J]. Nat Med, 2009, 15(6): 623-625. DOI: 10.1038/nm.1959.
46. Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis[J]. Proc Natl Acad Sci USA, 2010, 107(36): 15880-15885. DOI: 10.1073/pnas.1005743107.
47. Wong SL, 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.
48. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, et al. NETsare a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis[J/OL]. Sci Transl Med, 2013, 5(178): 178ra40[2013-04-27]. https://pubmed.ncbi.nlm.nih.gov/23536012/. DOI: 10.1126/scitranslmed.3005580.
49. Cools-Lartigue J, Spicer J, McDonald B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis[J]. J Clin Invest, 2013, 123(8): 3446-3458. DOI: 10.1172/JCI67484.
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