Inflammation and oxidative stress in diabetic retinopathy: pathogenic mechanisms and therapeutic perspectives_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Yuzhen ^1,2 , Yang Mulin ^2,3 , Zhu Yujie ¹ , GongCan ² ,  Wang Guifang ²

1. Medical College of Jishou University, Jishou 416000, China;
2. Loudi Central Hospital, Loudi 417000, China;
3. Hengyang Medical College, University of South China, Hengyang 421001, China;

Corresponding author：

Wang Guifang, Email: 85403659@qq.com

Keywords：

Diabetic retinopathy; Immune cells; Inflammatory mediators; Review

DOI：

10.3760/cma.j.cn511434-20250411-00163

Video：

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Abstract Full text Figures/Tables Video References Cited by

Diabetic retinopathy (DR) is the most common microvascular complication in patients with diabetes and a leading cause of vision loss. Recent studies have shown that inflammation and oxidative stress play central roles in its development and progression. Hyperglycemia activates systemic immune cells and retinal resident cells, inducing the release of various inflammatory mediators and chemokines, which disrupt the blood-retinal barrier, leading to capillary leakage and neurodegenerative changes. Meanwhile, the positive feedback loop between inflammation and reactive oxygen species/nitric oxide further amplifies pathological damage, explaining the limited efficacy of anti-vascular endothelial growth factor monotherapy. Oxidative stress manifests as the excessive generation of free radicals such as reactive oxygen species due to hyperglycemia, directly damaging retinal cells and activating inflammatory signaling pathways, thereby exacerbating vascular damage and neurodegeneration. Future therapeutic strategies should adopt multi-target and multi-link interventions, with particular emphasis on the combined application of anti-inflammatory and antioxidant treatments, such as immunomodulation, macrophage phenotype regulation, intervention in the neutrophil extracellular trap axis, and combination therapy using anti-vascular endothelial growth factor drugs and antioxidants, to more effectively intervene in the pathological progression of DR.

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1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy[J]. Lancet, 2010, 376(9735): 124-136. DOI: 10.1016/S0140-6736(09)62124-3.
2. Madjedi K, Pereira A, Ballios BG, et al. Switching between anti-VEGF agents in the management of refractory diabetic macular edema: a systematic review[J]. Surv Ophthalmol, 2022, 67(5): 1364-1372. DOI: 10.1016/j.survophthal.2022.04.001.
3. Kinuthia UM, Wolf A, Langmann T. Microglia and inflammatory responses in diabetic retinopathy[J/OL]. Front Immunol, 2020, 11: 564077[2020-11-06]. https://pubmed.ncbi.nlm.nih.gov/33240260/. DOI: 10.3389/fimmu.2020.564077.
4. Koleva-Georgieva DN, Sivkova NP, Terzieva D. Serum inflammatory cytokines IL-1β, IL-6, TNF-α and VEGF have influence on the development of diabetic retinopathy[J]. Folia Med (Plovdiv), 2011, 53(2): 44-50. DOI: 10.2478/v10153-010-0036-8.
5. Kowluru RA. Diabetic retinopathy and NADPH oxidase-2: a sweet slippery road[J/OL]. Antioxidants (Basel), 2021, 10(5): 783[2021-50-15]. https://pubmed.ncbi.nlm.nih.gov/34063353/. DOI: 10.3390/antiox10050783.
6. Pan X, Tan X, McDonald J, et al. Chemokines in diabetic eye disease[J/OL]. Diabetol Metab Syndr, 2024, 16(1): 115[2024-05-24]. https://pubmed.ncbi.nlm.nih.gov/38790059/. DOI: 10.1186/s13098-024-01297-w.
7. Li X, Zhang Y, Zhang Y, et al. CD8+ T cells promote pathological angiogenesis in ocular neovascular diseases[J]. J Immunol, 2022, 208(5): 1234-1245. DOI: 10.4049/jimmunol.2101234.
8. McPherson SW, Yang J, Chan CC, et al. Resting CD8 T cells recognize beta-galactosidase expressed in the immune-privileged retina and mediate autoimmune disease when activated[J]. Immunology, 2003, 110(3): 386-396. DOI: 10.1046/j.1365-2567.2003.01750.x.
9. Liu Y, Yang Z, Lai P, et al. Bcl-6-directed follicular helper T cells promote vascular inflammatory injury in diabetic retinopathy[J]. Theranostics, 2020, 10(9): 4250-4264. DOI: 10.7150/thno.43731.
10. Yu H, Liu B, Wu G, et al. Dysregulation of circulating follicular helper T cells in type 2 diabetic patients with diabetic retinopathy[J]. Immunol Res, 2021, 69(2): 153-161. DOI: 10.1007/s12026-021-09182-8.
11. Torres-Castro I, Arroyo-Camarena ÚD, Martínez-Reyes CP, et al. Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose[J]. Immunol Lett, 2016, 176: 81-89. DOI: 10.1016/j.imlet.2016.06.001.
12. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation[J]. Nat Rev Immunol, 2008, 8(12): 958-969. DOI: 10.1038/nri2448.
13. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment[J/OL]. F1000Prime Rep, 2014, 6: 13[2014-03-03]. https://pubmed.ncbi.nlm.nih.gov/24669294/. DOI: 10.12703/P6-13.
14. Mantovani A, Biswas SK, Galdiero MR, et al. Macrophage plasticity and polarization in tissue repair and remodelling[J]. J Pathol, 2013, 229(2): 176-185. DOI: 10.1002/path.4133.
15. Meng Z, Chen Y, Wu W, et al. Exploring the immune infiltration landscape and M2 macrophage-related biomarkers of proliferative diabetic retinopathy[J/OL]. Front Endocrinol (Lausanne), 2022, 13: 841813[2022-05-27]. https://pubmed.ncbi.nlm.nih.gov/35692390/. DOI: 10.3389/fendo.2022.841813.
16. 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.
17. Gui F, You Z, Fu S, et al. Endothelial dysfunction in diabetic retinopathy[J/OL]. Front Endocrinol (Lausanne), 2020, 11: 591[2020-09-04]. https://pubmed.ncbi.nlm.nih.gov/33013692/. DOI: 10.3389/fendo.2020.00591.
18. Liang WJ, Yang HW, Liu HN, et al. HMGB1 upregulates NF-kB by inhibiting IKB-α and associates with diabetic retinopathy[J/OL]. Life Sci, 2020, 241: 117146[2020-01-15]. https://pubmed.ncbi.nlm.nih.gov/31816325/. DOI: 10.1016/j.lfs.2019.117146.
19. Liu H, Ghosh S, Vaidya T, et al. Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy[J/OL]. JCI Insight, 2023, 8(12): e168945[2023-06-22]. https://pubmed.ncbi.nlm.nih.gov/37345657/. DOI: 10.1172/jci.insight.168945.
20. Yao X, Zhao Z, Zhang W, et al. Specialized retinal endothelial cells modulate blood-retina barrier in diabetic retinopathy[J]. Diabetes, 2024, 73(2): 225-236. DOI: 10.2337/db23-0368.
21. Hammes HP, Lin J, Renner O, et al. Pericytes and the pathogenesis of diabetic retinopathy[J]. Diabetes, 2002, 51(10): 3107-3112. DOI: 10.2337/diabetes.51.10.3107.
22. Dharmarajan S, Carrillo C, Qi Z, et al. Retinal inflammation in murine models of type 1 and type 2 diabetes with diabetic retinopathy[J]. Diabetologia, 2023, 66(11): 2170-2185. DOI: 10.1007/s00125-023-05995-4.
23. van Splunder H, Villacampa P, Martínez-Romero A, et al. Pericytes in the disease spotlight[J]. Trends Cell Biol, 2024, 34(1): 58-71. DOI: 10.1016/j.tcb.2023.06.001.
24. Kowluru RA, Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy[J]. Biochim Biophys Acta, 2015, 1852(11): 2474-2483. DOI: 10.1016/j.bbadis.2015.08.001.
25. Tang L, Xu GT, Zhang JF. Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy[J]. Neural Regen Res, 2023, 18(5): 976-982. DOI: 10.4103/1673-5374.355743.
26. Wang M, Ma W, Zhao L, et al. Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina[J/OL]. J Neuroinflammation, 2011, 8: 173[2011-12-07]. https://pubmed.ncbi.nlm.nih.gov/22152278/. DOI: 10.1186/1742-2094-8-173.
27. Liu Y, Li L, Pan N, et al. TNF-α released from retinal Müller cells aggravates retinal pigment epithelium cell apoptosis by upregulating mitophagy during diabetic retinopathy[J]. Biochem Biophys Res Commun, 2021, 561: 143-150. DOI: 10.1016/j.bbrc.2021.05.027.
28. Yang S, Qi S, Wang C. The role of retinal Müller cells in diabetic retinopathy and related therapeutic advances[J/OL]. Front Cell Dev Biol, 2022, 10: 1047487[2022-12-02]. https://pubmed.ncbi.nlm.nih.gov/36531955/. DOI: 10.3389/fcell.2022.1047487.
29. Yao Y, Li J, Zhou Y, et al. Macrophage/microglial polarization for the treatment of diabetic retinopathy[J/OL]. Front Endocrinol (Lausanne), 2023, 14: 1276225[2023-09-28]. https://pubmed.ncbi.nlm.nih.gov/37842315/. DOI: 10.3389/fendo.2023.1276225.
30. Mei X, Zhou L, Zhang T, et al. Chlorogenic acid attenuates diabetic retinopathy by reducing VEGF expression and inhibiting VEGF-mediated retinal neoangiogenesis[J]. Vascul Pharmacol, 2018, 101: 29-37. DOI: 10.1016/j.vph.2017.11.002.
31. Demircan N, Safran BG, Soylu M, et al. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy[J]. Eye (Lond), 2006, 20(12): 1366-1369. DOI: 10.1038/sj.eye.6702138.
32. Johnsen-Soriano S, Sancho-Tello M, Arnal E, et al. IL-2 and IFN-gamma in the retina of diabetic rats[J]. Graefe's Arch Clin Exp Ophthalmol, 2010, 248(7): 985-990. DOI: 10.1007/s00417-009-1289-x.
33. Chung YR, Kim YH, Ha SJ, et al. Role of inflammation in classification of diabetic macular edema by optical coherence tomography[J/OL]. J Diabetes Res, 2019, 2019: 8164250[2019-12-20]. https://pubmed.ncbi.nlm.nih.gov/31930145/. DOI: 10.1155/2019/8164250.
34. Yu H, Huang X, Ma Y, et al. Interleukin-8 regulates endothelial permeability by down-regulation of tight junction but not dependent on integrins induced focal adhesions[J]. Int J Biol Sci, 2013, 9(9): 966-979. DOI: 10.7150/ijbs.6996.
35. Silvestre JS, Mallat Z, Duriez M, et al. Antiangiogenic effect of interleukin-10 in ischemia-induced angiogenesis in mice hindlimb[J]. Circ Res, 2000, 87(6): 448-452. DOI: 10.1161/01.res.87.6.448.
36. Behl Y, Krothapalli P, Desta T, et al. Diabetes-enhanced tumor necrosis factor-alpha production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy[J]. Am J Pathol, 2008, 172(5): 1411-1418. DOI: 10.2353/ajpath.2008.071070.
37. Ishida S, Usui T, Yamashiro K, et al. VEGF164 is proinflammatory in the diabetic retina[J]. Invest Ophthalmol Vis Sci, 2003, 44(5): 2155-2162. DOI: 10.1167/iovs.02-0807.
38. Wang J, Xu X, Elliott MH, et al. Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage[J]. Diabetes, 2010, 59(9): 2297-2305. DOI: 10.2337/db09-1420.
39. Huang H, He J, Johnson D, et al. Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition[J]. Diabetes, 2015, 64(1): 200-212. DOI: 10.2337/db14-0016.
40. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation[J]. Nat Med, 2006, 12(2): 235-239. DOI: 10.1038/nm1351.
41. Murugeswari P, Shukla D, Rajendran A, et al. Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and Eales' disease[J]. Retina, 2008, 28(6): 817-824. DOI: 10.1097/IAE.0b013e31816576d5.
42. Calderon GD, Juarez OH, Hernandez GE, et al. Oxidative stress and diabetic retinopathy: development and treatment[J]. Eye (Lond), 2017, 31(8): 1122-1130. DOI: 10.1038/eye.2017.64.
43. Abu El-Asrar AM, Desmet S, Meersschaert A, et al. Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus[J]. Am J Ophthalmol, 2001, 132(4): 551-556. DOI: 10.1016/s0002-9394(01)01127-8.
44. Yang D, Elner SG, Bian ZM, et al. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells[J]. Exp Eye Res, 2007, 85(4): 462-472. DOI: 10.1016/j.exer.2007.06.013.
45. Grau GE, Thompson MB, Murphy CR. VEGF: inflammatory paradoxes[J]. Pathog Glob Health, 2015, 109(6): 253-254. DOI: 10.1179/2047772415Z.000000000271.
46. Tang X, Yang Y, Yuan H, et al. Novel transcriptional regulation of VEGF in inflammatory processes[J]. J Cell Mol Med, 2013, 17(3): 386-397. DOI: 10.1111/jcmm.12020.
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48. Yoda-Murakami M, Taniguchi M, Takahashi K, et al. Change in expression of GBP28/adiponectin in carbon tetrachloride-administrated mouse liver[J]. Biochem Biophys Res Commun, 2001, 285(2): 372-377. DOI: 10.1006/bbrc.2001.5134.
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