Lipocalin 2 Induces Visual Impairment by Promoting Ferroptosis in Retinal Ischemia-reperfusion Injury

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2023 Feb 10

PMID 36760251

Authors

Tingfang Mei

Jinwen Wu

Keling Wu

Minglei Zhao

Jingyi Luo

Xinqi Liu

Bizhi Shang

Wenchang Xu

Zeqiu Yang

Yuhua Lai

Chujun Liu

Haijun Gong

Xinbo Gao

Yehong Zhuo

Mingkai Lin

Ling Zhao

Affiliations

Soon will be listed here.

Abstract

Background: Retinal ischemia-reperfusion (RIR) is a common pathological condition that can lead to retinal ganglion cell (RGC) death and visual impairment. However, the pathogenesis of RGC loss and visual impairment caused by retinal ischemia remains unclear.

Methods: A mouse model of elevated intraocular pressure (IOP)-induced RIR injury was used. Flash visual evoked potentials (FVEPs) and electroretinography (ERG) recordings were performed to assess visual function. The structural integrity of the retina and the number of RGC were assessed using hematoxylin and eosin (HE) staining and retinal flat mounts. Ferroptosis was evaluated by testing the levels of glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPX4), and ferritin light chains (FTL) in the retina of wild-type (WT) and lipocalin-2 transgenic () mice after RIR injury.

Results: We found that LCN2 was mainly expressed in the RGC layer in the retina of wild-type mice and remarkably upregulated after RIR injury. Compared with wild-type mice, aggravated RGC death and visual impairment were exhibited in mice with RIR injury. Moreover, LCN2 overexpression activated glial cells and upregulated proinflammatory factors. More importantly, we found that LCN2 strongly promoted ferroptosis signaling in RGC death and visual impairment. Liproxstatin-1, an inhibitor of ferroptosis, could significantly ameliorate RGC death and visual impairment. Furthermore, we found significantly alleviated RGC death and retinal damage in LCN2 heterozygous knockout mice.

Conclusions: Our study provides important insights linking upregulated LCN2-mediated promotion of ferroptosis to RGC death and visual function impairment in the pathogenesis of ischemic retinopathy.

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References

Gupta U, Ghosh S, Wallace C, Shang P, Xin Y, Nair A . Increased LCN2 (lipocalin 2) in the RPE decreases autophagy and activates inflammasome-ferroptosis processes in a mouse model of dry AMD. Autophagy. 2022; 19(1):92-111. PMC: 9809950. DOI: 10.1080/15548627.2022.2062887. View

Yoneshige A, Hagiyama M, Takashima Y, Ueno S, Inoue T, Kimura R . Elevated Hydrostatic Pressure Causes Retinal Degeneration Through Upregulating Lipocalin-2. Front Cell Dev Biol. 2021; 9:664327. PMC: 8201777. DOI: 10.3389/fcell.2021.664327. View

Dekens D, Eisel U, Gouweleeuw L, Schoemaker R, De Deyn P, Naude P . Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases. Ageing Res Rev. 2021; 70:101414. DOI: 10.1016/j.arr.2021.101414. View

Hambright W, Fonseca R, Chen L, Na R, Ran Q . Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017; 12:8-17. PMC: 5312549. DOI: 10.1016/j.redox.2017.01.021. View

Fan B, Pang Y, Li W, Zhao C, Zhang Y, Wang X . Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen Res. 2020; 16(3):561-566. PMC: 7996026. DOI: 10.4103/1673-5374.293157. View

Luo J, Zhao L, Chen A, Zhang X, Zhu J, Zhao J . TCF7L2 variation and proliferative diabetic retinopathy. Diabetes. 2013; 62(7):2613-7. PMC: 3712060. DOI: 10.2337/db12-1093. View

Toychiev A, Batsuuri K, Srinivas M . Gap Junctional Coupling Between Retinal Astrocytes Exacerbates Neuronal Damage in Ischemia-Reperfusion Injury. Invest Ophthalmol Vis Sci. 2021; 62(14):27. PMC: 8648063. DOI: 10.1167/iovs.62.14.27. View

Stockwell B, Friedmann Angeli J, Bayir H, Bush A, Conrad M, Dixon S . Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017; 171(2):273-285. PMC: 5685180. DOI: 10.1016/j.cell.2017.09.021. View

Ghosh S, Stepicheva N, Yazdankhah M, Shang P, Watson A, Hose S . The role of lipocalin-2 in age-related macular degeneration (AMD). Cell Mol Life Sci. 2020; 77(5):835-851. PMC: 7079812. DOI: 10.1007/s00018-019-03423-8. View

10.

Chang M, Wu C, Jiang-Shieh Y, Shieh J, Wen C . Reactive changes of retinal astrocytes and Müller glial cells in kainate-induced neuroexcitotoxicity. J Anat. 2007; 210(1):54-65. PMC: 2100256. DOI: 10.1111/j.1469-7580.2006.00671.x. View

11.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

12.

Obolensky A, Berenshtein E, Lederman M, Bulvik B, Alper-Pinus R, Yaul R . Zinc-desferrioxamine attenuates retinal degeneration in the rd10 mouse model of retinitis pigmentosa. Free Radic Biol Med. 2011; 51(8):1482-91. DOI: 10.1016/j.freeradbiomed.2011.07.014. View

13.

Chen H, Deng Y, Gan X, Li Y, Huang W, Lu L . NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Mol Neurodegener. 2020; 15(1):26. PMC: 7161290. DOI: 10.1186/s13024-020-00372-w. View

14.

Jo D, Kim J, Kim J . A platform of integrative studies from in vitro to in vivo experiments: towards drug development for ischemic retinopathy. Biomed Pharmacother. 2015; 69:367-73. DOI: 10.1016/j.biopha.2014.12.027. View

15.

Ueno S, Yoneshige A, Koriyama Y, Hagiyama M, Shimomura Y, Ito A . Early Gene Expression Profile in Retinal Ganglion Cell Layer After Optic Nerve Crush in Mice. Invest Ophthalmol Vis Sci. 2018; 59(1):370-380. DOI: 10.1167/iovs.17-22438. View

16.

Guiney S, Adlard P, Bush A, Finkelstein D, Ayton S . Ferroptosis and cell death mechanisms in Parkinson's disease. Neurochem Int. 2017; 104:34-48. DOI: 10.1016/j.neuint.2017.01.004. View

17.

Zhou Y, Que K, Zhang Z, Yi Z, Zhao P, You Y . Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl-p53 pathway. Cancer Med. 2018; 7(8):4012-4022. PMC: 6089144. DOI: 10.1002/cam4.1670. View

18.

Jang E, Lee S, Kim J, Kim J, Seo J, Lee W . Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J. 2012; 27(3):1176-90. DOI: 10.1096/fj.12-222257. View

19.

Ide S, Kobayashi Y, Ide K, Strausser S, Abe K, Herbek S . Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair. Elife. 2021; 10. PMC: 8318592. DOI: 10.7554/eLife.68603. View

20.

Jha M, Lee S, Park D, Kook H, Park K, Lee I . Diverse functional roles of lipocalin-2 in the central nervous system. Neurosci Biobehav Rev. 2014; 49:135-56. DOI: 10.1016/j.neubiorev.2014.12.006. View