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Resveratrol Ameliorates Retinal Ischemia-Reperfusion Injury by Modulating the NLRP3 Inflammasome and Keap1/Nrf2/HO-1 Signaling Pathway

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Abstract

Glaucoma, as an ischemia-reperfusion (I/R) injury disease, leading irreversible blindness through the loss of retinal ganglion cells (RGCs), mediated by various pathways. Resveratrol (Res) is a polyphenolic compound that exerts protective effects against I/R injury in many tissues. This article aimed to expound the underlying mechanisms through which Res protects RGCs and reduces visual dysfunction in vivo. An experimental glaucoma model was created using 6-8-week wild-type male C57BL/6J mice. Res was injected intraperitoneally for 5 days. The mice were then grouped according to the number of days after surgery and whether Res treatment was administered. We applied the Brn3a-labeled immunofluorescence staining and flash electroretinography (ERG) to assess the survival of RGCs and visual function. The expression of components of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, the interleukin-1-beta (IL-1β), and vital indicators of kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme-oxygenase 1 (HO-1) pathway at the protein and RNA levels were detected respectively. The survival of RGCs was reduced after surgery compared to controls, whereas Res application rescued RGCs and improved visual dysfunction. In conclusion, our results discovered that Res administration showed neuroprotective effects through inhibition of the NLRP3 inflammasome pathway and activation of Keap1/Nrf2/HO-1 pathway. Thus, we further elucidated the potential of Res in glaucoma therapy.

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Data Availability

All the data and results used in this study are available from the corresponding author on reasonable request.

References

  1. Schuster AK, Erb C, Hoffmann EM, Dietlein T, Pfeiffer N (2020) The diagnosis and treatment of glaucoma. Dtsch Arztebl Int 117(13):225–234. https://doi.org/10.3238/arztebl.2020.0225

    Article  PubMed  Google Scholar 

  2. Kang JM, Tanna AP (2021) Glaucoma. Med Clin North Am 105(3):493–510. https://doi.org/10.1016/j.mcna.2021.01.004

    Article  PubMed  Google Scholar 

  3. Stein JD, Khawaja AP, Weizer JS (2021) Glaucoma in adults-screening, diagnosis, and management: a review. JAMA 325(2):164–174. https://doi.org/10.1001/jama.2020.21899

    Article  PubMed  Google Scholar 

  4. Huang Y, Xu W, Zhou R (2021) NLRP3 inflammasome activation and cell death. Cell Mol Immunol 18(9):2114–2127. https://doi.org/10.1038/s41423-021-00740-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang L, Hauenstein AV (2020) The NLRP3 inflammasome: mechanism of action, role in disease and therapies. Mol Aspects Med 76:100889. https://doi.org/10.1016/j.mam.2020.100889

    Article  CAS  PubMed  Google Scholar 

  6. Wang M, Pan W, Xu Y, Zhang J, Wan J, Jiang H (2022) Microglia-mediated neuroinflammation: a potential target for the treatment of cardiovascular diseases. J Inflamm Res 15:3083–3094. https://doi.org/10.2147/JIR.S350109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shen S, Wang Z, Sun H, Ma L (2022) Role of NLRP3 inflammasome in myocardial ischemia-reperfusion injury and ventricular remodeling. Med Sci Monit 28:e934255. https://doi.org/10.12659/MSM.934255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8, Minutoli L, Puzzolo D, Rinaldi M, Irrera N, Marini H, Arcoraci V, Bitto A, Crea G et al (2016) ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxid Med Cell Longev 2016:2183026. https://doi.org/10.1155/2016/2183026

  9. Toldo S, Abbate A (2018) The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol 15(4):203–214. https://doi.org/10.1038/nrcardio.2017.161

    Article  CAS  PubMed  Google Scholar 

  10. Ulasov AV, Rosenkranz AA, Georgiev GP, Sobolev AS (2022) Nrf2/Keap1/ARE signaling: towards specific regulation. Life Sci 291:120111. https://doi.org/10.1016/j.lfs.2021.120111

    Article  CAS  PubMed  Google Scholar 

  11. Saha S, Buttari B, Panieri E, Profumo E, Saso L (2020) An overview of Nrf2 signaling pathway and its role in inflammation. Molecules 25(22). https://doi.org/10.3390/molecules25225474

  12. Panisello-Roselló GBR, Sanchez-Nuno A, Alva S, Roselló-Catafau N, Carbonell J T (2022) Nrf2 and oxidative stress in liver ischemia/reperfusion injury. Febs J 289(18):5463–5479. https://doi.org/10.1111/febs.16336

    Article  CAS  PubMed  Google Scholar 

  13. Yu C, Xiao JH (2021) The Keap1-Nrf2 system: a mediator between oxidative stress and aging. Oxid Med Cell Longev 2021:6635460. https://doi.org/10.1155/2021/6635460

  14. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73(17):3221–3247. https://doi.org/10.1007/s00018-016-2223-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang Q, Liu J, Duan H, Li R, Peng W, Wu C (2021) Activation of Nrf2/HO-1 signaling: an important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. J Adv Res 34:43–63. https://doi.org/10.1016/j.jare.2021.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang C, Zhao M, Wang B, Su Z, Guo B, Qin L, Zhang W, Zheng R (2021) The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of celastrol in Parkinson’s disease. Redox Biol 47:102134. https://doi.org/10.1016/j.redox.2021.102134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bian H, Wang G, Huang J, Liang L, Zheng Y, Wei Y, Wang H, Xiao L et al (2020) Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/NLRP3 signaling in rat. J Neuroinflammation 17(1):166. https://doi.org/10.1186/s12974-020-01836-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wu Y, Qiu G, Zhang H, Zhu L, Cheng G, Wang Y, Li Y, Wu W (2021) Dexmedetomidine alleviates hepatic ischaemia-reperfusion injury via the PI3K/AKT/Nrf2-NLRP3 pathway. J Cell Mol Med 25(21):9983–9994. https://doi.org/10.1111/jcmm.16871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xiao L, Dai Z, Tang W, Liu C, Tang B (2021) Astragaloside IV alleviates cerebral ischemia-reperfusion injury through NLRP3 inflammasome-mediated pyroptosis inhibition via activating Nrf2. Oxid Med Cell Longev 2021:9925561. https://doi.org/10.1155/2021/9925561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cheng Y, Cheng L, Gao X, Chen S, Wu P, Wang C, Liu Z (2021) Covalent modification of Keap1 at Cys77 and Cys434 by pubescenoside a suppresses oxidative stress-induced NLRP3 inflammasome activation in myocardial ischemia-reperfusion injury. Theranostics 11(2):861–877. https://doi.org/10.7150/thno.48436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qi Y, Zhao M, Bai Y, Huang L, Yu W, Bian Z, Zhao M, Li X (2014) Retinal ischemia/reperfusion injury is mediated by toll-like receptor 4 activation of NLRP3 inflammasomes. Invest Ophthalmol Vis Sci 55(9):5466–5475. https://doi.org/10.1167/iovs.14-14380

    Article  CAS  PubMed  Google Scholar 

  22. Su CF, Jiang L, Zhang XW, Iyaswamy A, Li M (2021) Resveratrol in rodent models of Parkinson’s disease: a systematic review of experimental studies. Front Pharmacol 12:644219. https://doi.org/10.3389/fphar.2021.644219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hecker A, Schellnegger M, Hofmann E, Luze H, Nischwitz SP, Kamolz LP, Kotzbeck P (2022) The impact of resveratrol on skin wound healing, scarring, and aging. Int Wound J 19(1):9–28. https://doi.org/10.1111/iwj.13601

    Article  PubMed  Google Scholar 

  24. Khorshidi F, Poljak A, Liu Y, Lo JW, Crawford JD, Sachdev PS (2021) Resveratrol: a miracle drug in neuropsychiatry or a cognitive enhancer for mice only? A systematic review and meta-analysis. Ageing Res Rev 65:101199. https://doi.org/10.1016/j.arr.2020.101199

    Article  CAS  PubMed  Google Scholar 

  25. Mahdavi A, Bagherniya M, Mirenayat MS, Atkin SL, Sahebkar A (2021) Medicinal plants and phytochemicals regulating insulin resistance and glucose homeostasis in type 2 diabetic patients: a clinical review. Adv Exp Med Biol 1308:161–183. https://doi.org/10.1007/978-3-030-64872-5_13

    Article  CAS  PubMed  Google Scholar 

  26. Sun ZM, Guan P, Luo LF, Qin LY, Wang N, Zhao YS, Ji ES (2020) Resveratrol protects against CIH-induced myocardial injury by targeting Nrf2 and blocking NLRP3 inflammasome activation. Life Sci 245:117362. https://doi.org/10.1016/j.lfs.2020.117362

    Article  CAS  PubMed  Google Scholar 

  27. Ji K, Li Z, Lei Y, Xu W, Ouyang L, He T, Xing Y (2021) Resveratrol attenuates retinal ganglion cell loss in a mouse model of retinal ischemia reperfusion injury via multiple pathways. Exp Eye Res 209:108683. https://doi.org/10.1016/j.exer.2021.108683

    Article  CAS  PubMed  Google Scholar 

  28. Sun YY, Zhu HJ, Zhao RY, Zhou SY, Wang MQ, Yang Y, Guo ZN (2023) Remote ischemic conditioning attenuates oxidative stress and inflammation via the Nrf2/HO-1 pathway in MCAO mice. Redox Biol 66:102852. https://doi.org/10.1016/j.redox.2023.102852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li J, Xu P, Hong Y, Xie Y, Peng M, Sun R, Guo H, Zhang X et al (2023) Lipocalin-2-mediated astrocyte pyroptosis promotes neuroinflammatory injury via NLRP3 inflammasome activation in cerebral ischemia/reperfusion injury. J Neuroinflammation 20(1):148. https://doi.org/10.1186/s12974-023-02819-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hu R, Luo H, Ji Y, Wang Z, Zheng P, Ouyang H, Wang X, Wang Y et al (2023) Activation of NLRP3 signaling contributes to cadmium-induced bone defects, associated with autophagic flux obstruction. Sci Total Environ 893:164787. https://doi.org/10.1016/j.scitotenv.2023.164787

    Article  CAS  PubMed  Google Scholar 

  31. Yang J, Yang N, Luo J, Cheng G, Zhang X, He T, Xing Y (2020) Overexpression of S100A4 protects retinal ganglion cells against retinal ischemia-reperfusion injury in mice. Exp Eye Res 201:108281. https://doi.org/10.1016/j.exer.2020.108281

    Article  CAS  PubMed  Google Scholar 

  32. Franke M, Bieber M, Kraft P, Weber A, Stoll G, Schuhmann MK (2021) The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain Behav Immun 92:223–233. https://doi.org/10.1016/j.bbi.2020.12.009

    Article  CAS  PubMed  Google Scholar 

  33. Tang TT, Lv LL, Pan MM, Wen Y, Wang B, Li ZL, Wu M, Wang FM et al (2018) Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation. Cell Death Dis 9(3):351. https://doi.org/10.1038/s41419-018-0378-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Qin Q, Yu N, Gu Y, Ke W, Zhang Q, Liu X, Wang K, Chen M (2022) Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury. Cell Death Dis 13(5):507. https://doi.org/10.1038/s41419-022-04911-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M (2022) Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther 7(1):131. https://doi.org/10.1038/s41392-022-00955-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Madhu LN, Kodali M, Attaluri S, Shuai B, Melissari L, Rao X, Shetty AK (2021) Melatonin improves brain function in a model of chronic Gulf War illness with modulation of oxidative stress, NLRP3 inflammasomes, and BDNF-ERK-CREB pathway in the hippocampus. Redox Biol 43:101973. https://doi.org/10.1016/j.redox.2021.101973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sharma BR, Kanneganti TD (2021) NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol 22(5):550–559. https://doi.org/10.1038/s41590-021-00886-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen H, Deng Y, Gan X, Li Y, Huang W, Lu L, Wei L, Su L et al (2020) NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Mol Neurodegener 15(1):26. https://doi.org/10.1186/s13024-020-00372-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu M, Li H, Yang R, Ji D, Xia X (2022) GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma. J Neuroinflammation 19(1):262. https://doi.org/10.1186/s12974-022-02626-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu J, Zhang N, Zhang M, Yin H, Zhang X, Wang X, Wang X, Zhao Y (2021) N-acetylserotonin alleviated the expression of interleukin-1β in retinal ischemia-reperfusion rats via the TLR4/NF-κB/NLRP3 pathway. Exp Eye Res 208:108595. https://doi.org/10.1016/j.exer.2021.108595

    Article  CAS  PubMed  Google Scholar 

  41. Zhao W, Huang X, Han X, Hu D, Hu X, Li Y, Huang P, Yao W (2018) Resveratrol suppresses gut-derived NLRP3 inflammasome partly through stabilizing mast cells in a rat model. Mediators Inflamm 2018:6158671. https://doi.org/10.1155/2018/6158671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. He Q, Li Z, Wang Y, Hou Y, Li L, Zhao J (2017) Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. Int Immunopharmacol 50:208–215. https://doi.org/10.1016/j.intimp.2017.06.029

    Article  CAS  PubMed  Google Scholar 

  43. Li H, Zheng F, Zhang Y, Sun J, Gao F, Shi G (2022) Resveratrol, novel application by preconditioning to attenuate myocardial ischemia/reperfusion injury in mice through regulate AMPK pathway and autophagy level. J Cell Mol Med 26(15):4216–4229. https://doi.org/10.1111/jcmm.17431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rojo DLVM, Chapman E, Zhang DD (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34(1):21–43. https://doi.org/10.1016/j.ccell.2018.03.022

    Article  CAS  Google Scholar 

  45. Qin X, Li N, Zhang M, Lin S, Zhu J, Xiao D, Cui W, Zhang T et al (2019) Tetrahedral framework nucleic acids prevent retina ischemia-reperfusion injury from oxidative stress via activating the Akt/Nrf2 pathway. Nanoscale 11(43):20667–20675. https://doi.org/10.1039/c9nr07171g

    Article  CAS  PubMed  Google Scholar 

  46. Arioz BI, Tastan B, Tarakcioglu E, Tufekci KU, Olcum M, Ersoy N, Bagriyanik A, Genc K et al (2019) Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 inflammasome activation through the SIRT1/Nrf2 pathway. Front Immunol 10:1511. https://doi.org/10.3389/fimmu.2019.01511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang H, Lv H, Li H, Ci X, Peng L (2019) Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-κB pathways. Cell Commun Signal 17(1):62. https://doi.org/10.1186/s12964-019-0366-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lin Y, Luo T, Weng A, Huang X, Yao Y, Fu Z, Li Y, Liu A et al (2020) Gallic acid alleviates gouty arthritis by inhibiting NLRP3 inflammasome activation and pyroptosis through enhancing Nrf2 signaling. Front Immunol 11:580593. https://doi.org/10.3389/fimmu.2020.580593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Satoh T, Trudler D, Oh CK, Lipton SA (2022) Potential therapeutic use of the rosemary diterpene carnosic acid for Alzheimer’s disease, Parkinson’s disease, and Long-COVID through NRF2 activation to counteract the NLRP3 inflammasome. Antioxid (Basel) 11(1). https://doi.org/10.3390/antiox11010124

  50. Dai Y, Zhang J, Xiang J, Li Y, Wu D, Xu J (2019) Calcitriol inhibits ROS-NLRP3-IL-1β signaling axis via activation of Nrf2-antioxidant signaling in hyperosmotic stress stimulated human corneal epithelial cells. Redox Biol 21:101093. https://doi.org/10.1016/j.redox.2018.101093

    Article  CAS  PubMed  Google Scholar 

  51. Liu Q, Zhang F, Zhang X, Cheng R, Ma JX, Yi J, Li J (2018) Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation. Mol Cell Biochem 445(1–2):105–115. https://doi.org/10.1007/s11010-017-3256-x

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

Funding

This work was granted by the National Natural Science Foundation of China (No. 81271025 and 81860170).

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Author notes

  1. Jiazhen Feng and Kaibao Ji contributed equally to this study.

Authors and Affiliations

  1. Department of Ophthalmology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China

    Jiazhen Feng, Kaibao Ji, Yiji Pan, Pingping Huang, Tao He & Yiqiao Xing

  2. Eye Institute of Wuhan University, Hubei, China

    Jiazhen Feng, Kaibao Ji, Yiji Pan & Yiqiao Xing

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  1. Jiazhen Feng
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  2. Kaibao Ji
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Contributions

Design: Kaibao Ji and Yiqiao Xing. Research conduction: Jiazhen Feng, Kaibao Ji, Yiji Pan and Pingping Huang. Data collection and analysis: Kaibao Ji, Jiazhen Feng and Tao He. Figure preparation: Jiazhen Feng and Kaibao Ji. Study supervision: Tao He and Yiqiao Xing.

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Correspondence to Tao He or Yiqiao Xing.

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This study was performed in line with the principles of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Approval was granted by the Ethics Committee of the Renmin Hospital of Wuhan University.

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Feng, J., Ji, K., Pan, Y. et al. Resveratrol Ameliorates Retinal Ischemia-Reperfusion Injury by Modulating the NLRP3 Inflammasome and Keap1/Nrf2/HO-1 Signaling Pathway. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04105-8

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