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Activated microglia–induced neuroinflammatory cytokines lead to photoreceptor apoptosis in Aβ-injected mice

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Abstract

Age-related macular degeneration (AMD) is mainly characterized by the progressive accumulation of drusen deposits and loss of photoreceptors and retinal pigment epithelial (RPE) cells. Because amyloid β (Aβ) is the main component of drusen, Aβ-induced activated microglia most likely lead to neuroinflammation and play a critical role in the pathogenesis of AMD. However, the relationship between activated microglia–mediated neuroinflammatory cytokines and photoreceptor death has not been clarified. By subretinal injection of Aβ42 in mice, we mimicked an inflammatory milieu of AMD to better understand how activated microglia–induced neuroinflammatory cytokines lead to photoreceptor apoptosis in the AMD progression. We demonstrated that subretinal injection of Aβ42 induces microglial activation and increases inflammatory cytokine release, which gives rise to photoreceptor apoptosis in mice. Our results were verified in vitro by co-culture of Aβ42 activated primary microglia and the photoreceptor cell line 661W. We also demonstrated that the p38 mitogen-activated protein kinase (MAPK) signaling pathway was involved in Aβ42-induced microglial activation and inflammatory cytokine release. Overall, our findings indicate that activated microglia–derived neuroinflammatory cytokines could contribute to photoreceptor apoptosis under the stimulation of Aβ42. Moreover, this study may provide a potential therapeutic approach for AMD.

Key messages

  • Further explore the association between activated microglia–derived neuroinflammatory cytokine secretion and photoreceptor apoptosis under the stimulation of Aβ42.

  • Subretinal injection of Aβ42 induces the activation of microglia and increases proinflammatory cytokines IL-1β and COX-2 expression in the retina, which could give rise to the deterioration of visual function and aggravate photoreceptor apoptosis in mice.

  • Primary microglial are activated and the levels of proinflammatory cytokines are increased by Aβ42 stimulation, which could increase the apoptosis of photoreceptor cell line 661W in vitro.

  • The p38 MAPK signaling pathway is involved in microglial activation and photoreceptor apoptosis under Aβ42 treatment.

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Data availability

Jingfa Zhang and Fang Liu are guarantors of this work, who have full access to all the data in this study and take responsibility for the integrity and accuracy of the data. Data are available from the corresponding authors on reasonable request.

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Acknowledgements

We are grateful to Binxin Wu (Tongji University School of Medicine, Shanghai, China) for technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China (81570852, 81870667, 81970810, 81970811), the Science and Technology Commission of Shanghai Municipality (19495800700), and the Clinical Research and Cultivation Project of Shanghai Municipal Hospital, China (SHDC12019X30).

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Author notes

  1. Fang Liu and Jingfa Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    Jing Wu, Sichang Qu, Fang Liu & Jingfa Zhang

  2. Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    Ge Gao

  3. Department of Ophthalmology, the Second Affiliated Hospital of Soochow University, Suzhou, China

    Fanjun Shi

  4. Department of Regenerative Medicine and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China

    Hai Xie, Qian Yang, Dandan Liu, Guo-Tong Xu & Jingfa Zhang

  5. Department of Ophthalmology, Shanghai Changhai Hospital, Shanghai, China

    Haifeng Qin

  6. Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University, Shanghai, China

    Chaoyang Zhang & Jingfa Zhang

  7. National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China

    Chaoyang Zhang & Jingfa Zhang

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  1. Jing Wu
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Contributions

Conception and design: Jingfa Zhang, Fang Liu, and Guo-Tong Xu.

Methodology: Jing Wu, Fanjun Shi, Qian Yang, Dandan Liu, Sichang Qu, and Haifeng Qin.

Data analysis: Jing Wu, Ge Gao, Hai Xie, Chaoyang Zhang, Jingfa Zhang, and Guo-Tong Xu.

Writing original draft preparation: Jing Wu and Jingfa Zhang.

Writing—review and editing: Fang Liu, Jingfa Zhang, and Guo-Tong Xu. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Fang Liu or Jingfa Zhang.

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All procedures involving the animal studies were approved (Permit Number: SHDSYY-2020-2938) and conducted in accordance with the guidelines of the Committee on the Ethics of Animal Experiments of Tongji University School of Medicine and adhered to the principles of the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

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Written informed consent for publication was obtained from all participants.

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Wu, J., Gao, G., Shi, F. et al. Activated microglia–induced neuroinflammatory cytokines lead to photoreceptor apoptosis in Aβ-injected mice. J Mol Med 99, 713–728 (2021). https://doi.org/10.1007/s00109-021-02046-6

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