Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis
CHU Fang-Fang, ZHAO Yan-Song, ZHAO Yu-Ze, BAI Chen, XIAO Pei-Lun, WANG Xiao-Li, YU Shu-Na, JIANG Ji-Ying
Department of Anatomy, Weifang Medical College, Weifang, Shandong 261053, China; Ophthalmology Center, Affiliated Hospital of Weifang Medical College, Weifang, Shandong 261031, China
Abstract Objective To study the protective effect of melatonin (Mel) against oxygen-induced retinopathy (OIR) in neonatal mice and the role of the HMGB1/NF-κB/NLRP3 axis. Methods Neonatal C57BL/6J mice, aged 7 days, were randomly divided into a control group, a model group (OIR group), and a Mel treatment group (OIR+Mel group), with 9 mice in each group. The hyperoxia induction method was used to establish a model of OIR. Hematoxylin and eosin staining and retinal flat-mount preparation were used to observe retinal structure and neovascularization. Immunofluorescent staining was used to measure the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis and lymphocyte antigen 6G. Colorimetry was used to measure the activity of myeloperoxidase. Results The OIR group had destruction of retinal structure with a large perfusion-free area and neovascularization, while the OIR+Mel group had improvement in destruction of retinal structure with reductions in neovascularization and perfusion-free area. Compared with the control group, the OIR group had significant increases in the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis, the expression of lymphocyte antigen 6G, and the activity of myeloperoxidase (P<0.05). Compared with the OIR group, the OIR+Mel group had significant reductions in the above indices (P<0.05). Compared with the control group, the OIR group had significant reductions in the expression of melatonin receptors in the retina (P<0.05). Compared with the OIR group, the OIR+Mel group had significant increases in the expression of melatonin receptors (P<0.05). Conclusions Mel can alleviate OIR-induced retinal damage in neonatal mice by inhibiting the HMGB1/NF-κB/NLRP3 axis and may exert an effect through the melatonin receptor pathway.
CHU Fang-Fang,ZHAO Yan-Song,ZHAO Yu-Ze et al. Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis[J]. CJCP, 2023, 25(6): 645-652.
CHU Fang-Fang,ZHAO Yan-Song,ZHAO Yu-Ze et al. Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis[J]. CJCP, 2023, 25(6): 645-652.
Crooke A, Huete-Toral F, Colligris B, et al. The role and therapeutic potential of melatonin in age-related ocular diseases[J]. J Pineal Res, 2017, 63(2): e12430. PMID: 28658514. DOI: 10.1111/jpi.12430.
Xu Y, Cui K, Li J, et al. Melatonin attenuates choroidal neovascularization by regulating macrophage/microglia polarization via inhibition of RhoA/ROCK signaling pathway[J]. J Pineal Res, 2020, 69(1): e12660. PMID: 32323368. DOI: 10.1111/jpi.12660.
Xu Y, Lu X, Hu Y, et al. Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF-1α-VEGF pathway in oxygen-induced retinopathy mice[J]. J Pineal Res, 2018, 64(4): e12473. PMID: 29411894. DOI: 10.1111/jpi.12473.
Yan M, Wang H, Gu Y, et al. Melatonin exerts protective effects on diabetic retinopathy via inhibition of Wnt/β-catenin pathway as revealed by quantitative proteomics[J]. Exp Eye Res, 2021, 205: 108521. PMID: 33636209. DOI: 10.1016/j.exer.2021.108521.
Smith LE, Wesolowski E, McLellan A, et al. Oxygen-induced retinopathy in the mouse[J]. Invest Ophthalmol Vis Sci, 1994, 35(1): 101-111. PMID: 7507904.
Do?anlar ZB, Gü?lü H, ?ztopuz ?, et al. The role of melatonin in oxidative stress, DNA damage, apoptosis and angiogenesis in fetal eye under preeclampsia and melatonin deficiency stress[J]. Curr Eye Res, 2019, 44(10): 1157-1169. PMID: 31090463. DOI: 10.1080/02713683.2019.1619778.
Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies[J]. Ageing Res Rev, 2015, 24(Pt A): 29-39. PMID: 25641058. DOI: 10.1016/j.arr.2015.01.003.
Dvoriantchikova G, Hernandez E, Grant J, et al. The high-mobility group box-1 nuclear factor mediates retinal injury after ischemia reperfusion[J]. Invest Ophthalmol Vis Sci, 2011, 52(10): 7187-7194. PMID: 21828158. PMCID: PMC3207720. DOI: 10.1167/iovs.11-7793.
Wang Y, Gao S, Gao S, et al. Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy[J]. Cell Biosci, 2021, 11(1): 82. PMID: 33933165. PMCID: PMC8088655. DOI: 10.1186/s13578-021-00593-6.
Sui A, Chen X, Shen J, et al. Inhibiting the NLRP3 inflammasome with MCC950 ameliorates retinal neovascularization and leakage by reversing the IL-1β/IL-18 activation pattern in an oxygen-induced ischemic retinopathy mouse model[J]. Cell Death Dis, 2020, 11(10): 901. PMID: 33093455. PMCID: PMC7582915. DOI: 10.1038/s41419-020-03076-7.
Qi Y, Zhao M, Bai Y, et al. Retinal ischemia/reperfusion injury is mediated by toll-like receptor 4 activation of NLRP3 inflammasomes[J]. Invest Ophthalmol Vis Sci, 2014, 55(9): 5466-5475. PMID: 25097240. DOI: 10.1167/iovs.14-14380.
Baba K, Pozdeyev N, Mazzoni F, et al. Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor[J]. Proc Natl Acad Sci U S A, 2009, 106(35):15043-15048. PMID: 19706469. PMCID: PMC2736407. DOI: 10.1073/pnas.0904400106.
Jiang T, Chang Q, Cai J, et al. Protective effects of melatonin on retinal inflammation and oxidative stress in experimental diabetic retinopathy[J]. Oxid Med Cell Longev, 2016, 2016:3528274. PMID: 27143993. PMCID: PMC4837288. DOI: 10.1155/2016/3528274.