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Theranostics 2022; 12(15):6705-6722. doi:10.7150/thno.71038 This issue Cite

Research Paper

Inhibiting the activation of MAPK (ERK1/2) in stressed Müller cells prevents photoreceptor degeneration

Shaoxue Zeng^1,2, Ting Zhang¹, Yingying Chen^1,2, Joshua Chu-Tan^3,4, Kaiyu Jin⁵, So-Ra Lee¹, Michelle X Yam¹, Michele C Madigan^1,6, Nilisha Fernando^3,7, Adrian Cioanca^3,4, Fanfan Zhou⁸, Meidong Zhu^1,9, Junjun Zhang², Riccardo Natoli^3,4, Xiaohui Fan⁵, Ling Zhu^1✉, Mark C Gillies¹

1. Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
2. Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
3. The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia.
4. The Australian National University Medical School, Canberra, ACT 2601, Australia.
5. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
6. School of Optometry and Vision Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
7. Neuro-Immune Regulome Unit, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States.
8. School of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
9. New South Wales Organ and Tissue Donation Service, New South Wales Tissue Bank, Sydney Eye Hospital, Sydney, NSW 2006, Australia.

✉ Corresponding author: Ling Zhu. E-mail address: ling.zhuedu.au

Abstract

Rationale: Müller cells play an essential role in maintaining the health of retinal photoreceptors. Dysfunction of stressed Müller cells often results in photoreceptor degeneration. However, how these cells communicate under stress and the signalling pathways involved remain unclear. In this study, we inhibited the MAPK (ERK1/2) signalling, mainly activated in Müller cells, evaluated the protective effects on the photoreceptors and further explored the signalling communication between stressed Müller cells and degenerating photoreceptors.

Methods: We evaluated the changes of MAPK (ERK1/2) signalling and its downstream targets in human retinal explants treated with PD98059, a specific phosphorylated ERK1/2 inhibitor, by western blot and immunostaining. We further assessed photoreceptor degeneration by TUNEL staining and outer nuclear layer thickness. We also injected PD98059 into the eyes of mice exposed to photo-oxidative stress. We evaluated the protective effects on photoreceptor degeneration by optical coherence tomography (OCT) and electroretinography (ERG). The crosstalk between Müller cells and photoreceptors was further dissected based on the changes of transcription factors by RNA sequencing and protein profiles of multiple signalling pathways.

Results: We found that MAPK (ERK1/2) signalling was mainly activated in Müller cells under stress, both ex vivo and in vivo. PD98059 inhibited the phosphorylation of ERK1/2, reduced expression of the gliotic marker glial fibrillary acidic protein (GFAP) in Müller cells and increased levels of the neuroprotective factor, interphotoreceptor retinoid-binding protein (IRBP) in photoreceptors. Inhibition of pERK1/2 also reduced retinal photo-oxidative damage in mice retinas assessed by OCT and ERG. We also identified that the JAK/STAT3 signalling pathway might mediate signalling transduction from Müller cells to photoreceptors.

Conclusion: MAPK (ERK1/2) deactivation through chemical inhibition, mainly in stressed Müller cells, can alleviate gliosis in Müller cells and restore the expression of IRBP in photoreceptors, which appears to prevent retinal degeneration. Our findings suggested a new way to prevent photoreceptor degeneration by manipulating the stress response in Müller cells.

Keywords: PD98059, pERK1/2 inhibition, Müller cells, photoreceptor degeneration

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