Advances in the mechanism of photoreceptor cell death induced by inflammation in age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Wang Yusong ,  Sun Xiaodong

Department of Ophthalmology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Key Laboratory of Fundus Disease, Shanghai 200080, China;

Corresponding author：

Sun Xiaodong, Email: xdsun@sjtu.edu.cn

Keywords：

Macular degeneration/etiology; Inflammation; Photoreceptor cells; Cell death; Review

DOI：

10.3760/cma.j.cn511434-20190716-00226

Video：

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Abstract Full text Figures/Tables Video References Cited by

Photoreceptor cells are special retinal neurons with photo-transformation ability. Loss of photoreceptors in age-related macular degeneration (AMD) is secondary to RPE loss, leakage of serum components from the neovascularization and scar formation, which is one of the main mechanisms of irreversible visual impairment in patients with AMD. Many studies have shown that inflammatory environment is involved in the process of photoreceptor cell death. Aging, photooxidation injury and other factors affects the retinal microenvironment through different levels of mechanisms such as retinal pigment epithelial cells, retinal glial cells, hematogenous macrophages and inflammatory factors, which results in photoreceptor injuries and participates in the progression of AMD by drusen formation and neovascularization. This study reviews the research status and progress of inflammation and photoreceptor cell death, and provides new ideas for exploring the blinding mechanism and treatment strategies of AMD.

Citation： Wang Yusong, Sun Xiaodong. Advances in the mechanism of photoreceptor cell death induced by inflammation in age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2020, 36(10): 825-828. doi: 10.3760/cma.j.cn511434-20190716-00226 Copy

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5.	Chen M, Luo C, Zhao J, et al. Immune regulation in the aging retina[J]. Prog Retin Eye Res, 2019, 69: 159-172. DOI: 10.1016/j.preteyeres.2018.10.003.
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7.	Mecca C, Giambanco I, Donato R, et al. Microglia and aging: the role of the TREM2-DAP12 and CX3CL1-CX3CR1 axes[J/OL]. Int J Mol Sci, 2018, 19(1): 318[2018-01-22]. https://pubmed.ncbi.nlm.nih.gov/29361745/. DOI: 10.3390/ijms19010318.
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11.	Trichonas G, Murakami Y, Thanos A, et al. Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis[J]. Proc Natl Acad Sci USA, 2010, 107(50): 21695-21700. DOI: 10.1073/pnas.1009179107.
12.	Murakami Y, Notomi S, Hisatomi T, et al. Photoreceptor cell death and rescue in retinal detachment and degenerations[J]. Prog Retin Eye Res, 2013, 37: 114-140. DOI: 10.1016/j.preteyeres.2013.08.001.
13.	McBee JK, Palczewski K, Baehr W, et al. Confronting complexity: the interlink of phototransduction and retinoid metabolism in the vertebrate retina[J]. Prog Retin Eye Res, 2001, 20(4): 469-529. DOI: 10.1016/s1350-9462(01)00002-7.
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15.	Hageman GS, Luthert PJ, Victor Chong NH, et al. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration[J]. Prog Retin Eye Res, 2001, 20(6): 705-732. DOI: 10.1016/s1350-9462(01)00010-6.
16.	Vu KT, Zhang F, Hulleman JD. Conditional, genetically encoded, small molecule-regulated inhibition of NFκB signaling in RPE cells[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 4126-4137. DOI: 10.1167/iovs.17-22133.
17.	Sene A, Apte RS. Inflammation-induced photoreceptor cell death[J]. Adv Exp Med Biol, 2018, 1074: 203-208. DOI: 10.1007/978-3-319-75402-4_25.
18.	Salter MW, Stevens B. Microglia emerge as central players in brain disease[J]. Nat Med, 2017, 23(9): 1018-1027. DOI: 10.1038/nm.4397.
19.	Ma W, Coon S, Zhao L, et al. A2E accumulation influences retinal microglial activation and complement regulation[J]. Neurobiol Aging, 2013, 34(3): 943-960. DOI: 10.1016/j.neurobiolaging.2012.06.010.
20.	Kettenmann H, Hanisch UK, Noda M, et al. Physiology of microglia[J]. Physiol Rev, 2011, 91(2): 461-553. DOI: 10.1152/physrev.00011.2010.
21.	Zabel MK, Zhao L, Zhang Y, et al. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa[J]. Glia, 2016, 64(9): 1479-1491. DOI: 10.1002/glia.23016.
22.	Krausgruber T, Blazek K, Smallie T, et al. IRF5 promotes inflammatory macrophage polarization and Th1-Th17 responses[J]. Nat Immunol, 2011, 12(3): 231-238. DOI: 10.1038/ni.1990.
23.	Wang M, Wong WT. Microglia-Müller cell interactions in the retina[J]. Adv Exp Med Biol, 2014, 801: 333-338. DOI: 10.1007/978-1-4614-3209-8_42.
24.	Zhang S, Zhang S, Gong W, et al. Müller cell regulated microglial activation and migration in rats with N-Methyl-N-Nitrosourea-induced retinal degeneration[J/OL]. Front Neurosci, 2018, 12: 890[2018-12-03]. https://pubmed.ncbi.nlm.nih.gov/30559643/. DOI: 10.3389/fnins.2018.00890.
25.	Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia[J]. Nature, 2017, 541(7638): 481-487. DOI: 10.1038/nature21029.
26.	Nakamura R, Sene A, Santeford A, et al. IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis[J/OL]. Nat Commun, 2015, 6: 7847[2015-08-11]. https://pubmed.ncbi.nlm.nih.gov/26260587/. DOI: 10.1038/ncomms8847.
27.	Sennlaub F, Auvynet C, Calippe B, et al. CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice[J]. EMBO Mol Med, 2013, 5(11): 1775-1793. DOI: 10.1002/emmm.201302692.
28.	Xie J, Zhu R, Peng Y, et al. Tumor necrosis factor-alpha regulates photoreceptor cell autophagy after retinal detachment[J/OL]. Sci Rep, 2017, 7(1): 17108[2017-12-07]. https://pubmed.ncbi.nlm.nih.gov/29215050/. DOI: 10.1038/s41598-017-17400-3.
29.	Choudhury S, Nashine S, Bhootada Y, et al. Modulation of the rate of retinal degeneration in T17M RHO mice by reprogramming the unfolded protein response[J]. Adv Exp Med Biol, 2014, 801: 455-462. DOI: 10.1007/978-1-4614-3209-8_58.
30.	Al-Gayyar MM, Elsherbiny NM. Contribution of TNF-alpha to the development of retinal neurodegenerative disorders[J]. Eur Cytokine Netw, 2013, 24(1): 27-36. DOI: 10.1684/ecn.2013.0334.
31.	Kauppinen A, Paterno JJ, Blasiak J, et al. Inflammation and its role in age-related macular degeneration[J]. Cell Mol Life Sci, 2016, 73(9): 1765-1786. DOI: 10.1007/s00018-016-2147-8.
32.	王蕾, 张晓敏, 李筱荣. 单核细胞趋化蛋白在视网膜疾病中的表达和作用[J]. 中华眼底病杂志, 2016, 32(5): 564-566. DOI: 10.3760/cma.j.issn.1005-1015.2016.05.032.Wang L, Zhang XM, Li XR. The status and progress of studies on monocyte chemoattractant protein-1 in retinal diseases[J]. Chin J Ocul Fundus Dis, 2016, 32(5): 564-566. DOI: 10.3760/cma.j.issn.1005-1015.2016.05.032.
33.	Nakazawa T, Hisatomi T, Nakazawa C, et al. Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis[J]. Proc Natl Acad Sci USA, 2007, 104(7): 2425-2430. DOI: 10.1073/pnas.0608167104.
34.	刘舒. 抗血管内皮生长因子药物治疗湿性年龄相关性黄斑变性研究现状[J]. 中华实验眼科杂志, 2018, 36(12): 962-966. DOI: 10.3760/cma.j.issn.2095.0160.2018.12.014.Liu S. Research progress of anti-VEGF for the therapy in wet age-related macular degeneration[J]. Chin J Exp Ophthalmol, 2018, 36(12): 962-966. DOI: 10.3760/cma.j.issn.2095.0160.2018.12.014.
35.	Maguire MG, Martin DF, Ying GS, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2016, 123(8): 1751-1761. DOI: 10.1016/j.ophtha.2016.03.045.
36.	Miere A, Butori P, Cohen SY, et al. Vascular remodeling of choroidal neovascularization after anti-vascular endothelial growth factor therapy visualized on optical coherence tomography angiography[J]. Retina, 2019, 39(3): 548-557. DOI: 10.1097/IAE.0000000000001964.
37.	Wright AF, Chakarova CF, Abd El-Aziz MM, et al. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait[J]. Nat Rev Genet, 2010, 11(4): 273-284. DOI: 10.1038/nrg2717.

1. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP)[J]. Ophthalmology, 2013, 120(11): 2292-2299. DOI: 10.1016/j.ophtha.2013.03.046.
2. Guillonneau X, Eandi CM, Paques M, et al. On phagocytes and macular degeneration[J]. Prog Retin Eye Res, 2017, 61: 98-128. DOI: 10.1016/j.preteyeres.2017.06.002.
3. Wooff Y, Man SM, Aggio-Bruce R, et al. IL-1 family members mediate cell death, inflammation and angiogenesis in retinal degenerative diseases[J/OL]. Front Immunol, 2019, 10: 1618[2019-07-16]. https://pubmed.ncbi.nlm.nih.gov/31379825/. DOI: 10.3389/fimmu.2019.01618.
4. 刘芳, 李加青. 巨噬细胞极化与AMD的关系[J]. 中华实验眼科杂志, 2016, 34(1): 89-91. DOI: 10.3760/cma.j.issn.2095-0160.2016.01.019.Liu F, Li JQ. Relationship between macrophage polarization and age-related macular degeneration[J]. Chin J Exp Ophthalmol, 2016, 34(1): 89-91. DOI: 10.3760/cma.j.issn.2095-0160.2016.01.019.
5. Chen M, Luo C, Zhao J, et al. Immune regulation in the aging retina[J]. Prog Retin Eye Res, 2019, 69: 159-172. DOI: 10.1016/j.preteyeres.2018.10.003.
6. López-Luppo M, Catita J, Ramos D, et al. Cellular senescence is associated with human retinal microaneurysm formation during aging[J]. Invest Ophthalmol Vis Sci, 2017, 58(7): 2832-2842. DOI: 10.1167/iovs.16-20312.
7. Mecca C, Giambanco I, Donato R, et al. Microglia and aging: the role of the TREM2-DAP12 and CX3CL1-CX3CR1 axes[J/OL]. Int J Mol Sci, 2018, 19(1): 318[2018-01-22]. https://pubmed.ncbi.nlm.nih.gov/29361745/. DOI: 10.3390/ijms19010318.
8. Grabert K, Michoel T, Karavolos MH, et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging[J]. Nat Neurosci, 2016, 19(3): 504-516. DOI: 10.1038/nn.4222.
9. 朱佳丽, 汪育文, 李明翰, 等. 不同波长光照射对rd12和C57BL/6J小鼠视网膜光损伤的对比研究[J]. 中华眼底病杂志, 2012, 28(3): 276-280. DOI: 10.3760/cma.j.issn.1005-1015.2012.03.016.Zhu JL, Wang YW, Li MH, et al. Comparison the effects of different wavelength lights on the retina of rd12 and C57BL/6J mice[J]. Chin J Ocul Fundus Dis, 2012, 28(3): 276-280. DOI: 10.3760/cma.j.issn.1005-1015.2012.03.016.
10. Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex[J]. Mol Aspects Med, 2012, 33(4): 295-317. DOI: 10.1016/j.mam.2012.04.005.
11. Trichonas G, Murakami Y, Thanos A, et al. Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis[J]. Proc Natl Acad Sci USA, 2010, 107(50): 21695-21700. DOI: 10.1073/pnas.1009179107.
12. Murakami Y, Notomi S, Hisatomi T, et al. Photoreceptor cell death and rescue in retinal detachment and degenerations[J]. Prog Retin Eye Res, 2013, 37: 114-140. DOI: 10.1016/j.preteyeres.2013.08.001.
13. McBee JK, Palczewski K, Baehr W, et al. Confronting complexity: the interlink of phototransduction and retinoid metabolism in the vertebrate retina[J]. Prog Retin Eye Res, 2001, 20(4): 469-529. DOI: 10.1016/s1350-9462(01)00002-7.
14. Anderson DH, Mullins RF, Hageman GS, et al. A role for local inflammation in the formation of drusen in the aging eye[J]. Am J Ophthalmol, 2002, 134(3): 411-431. DOI: 10.1016/s0002-9394(02)01624-0.
15. Hageman GS, Luthert PJ, Victor Chong NH, et al. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration[J]. Prog Retin Eye Res, 2001, 20(6): 705-732. DOI: 10.1016/s1350-9462(01)00010-6.
16. Vu KT, Zhang F, Hulleman JD. Conditional, genetically encoded, small molecule-regulated inhibition of NFκB signaling in RPE cells[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 4126-4137. DOI: 10.1167/iovs.17-22133.
17. Sene A, Apte RS. Inflammation-induced photoreceptor cell death[J]. Adv Exp Med Biol, 2018, 1074: 203-208. DOI: 10.1007/978-3-319-75402-4_25.
18. Salter MW, Stevens B. Microglia emerge as central players in brain disease[J]. Nat Med, 2017, 23(9): 1018-1027. DOI: 10.1038/nm.4397.
19. Ma W, Coon S, Zhao L, et al. A2E accumulation influences retinal microglial activation and complement regulation[J]. Neurobiol Aging, 2013, 34(3): 943-960. DOI: 10.1016/j.neurobiolaging.2012.06.010.
20. Kettenmann H, Hanisch UK, Noda M, et al. Physiology of microglia[J]. Physiol Rev, 2011, 91(2): 461-553. DOI: 10.1152/physrev.00011.2010.
21. Zabel MK, Zhao L, Zhang Y, et al. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa[J]. Glia, 2016, 64(9): 1479-1491. DOI: 10.1002/glia.23016.
22. Krausgruber T, Blazek K, Smallie T, et al. IRF5 promotes inflammatory macrophage polarization and Th1-Th17 responses[J]. Nat Immunol, 2011, 12(3): 231-238. DOI: 10.1038/ni.1990.
23. Wang M, Wong WT. Microglia-Müller cell interactions in the retina[J]. Adv Exp Med Biol, 2014, 801: 333-338. DOI: 10.1007/978-1-4614-3209-8_42.
24. Zhang S, Zhang S, Gong W, et al. Müller cell regulated microglial activation and migration in rats with N-Methyl-N-Nitrosourea-induced retinal degeneration[J/OL]. Front Neurosci, 2018, 12: 890[2018-12-03]. https://pubmed.ncbi.nlm.nih.gov/30559643/. DOI: 10.3389/fnins.2018.00890.
25. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia[J]. Nature, 2017, 541(7638): 481-487. DOI: 10.1038/nature21029.
26. Nakamura R, Sene A, Santeford A, et al. IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis[J/OL]. Nat Commun, 2015, 6: 7847[2015-08-11]. https://pubmed.ncbi.nlm.nih.gov/26260587/. DOI: 10.1038/ncomms8847.
27. Sennlaub F, Auvynet C, Calippe B, et al. CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice[J]. EMBO Mol Med, 2013, 5(11): 1775-1793. DOI: 10.1002/emmm.201302692.
28. Xie J, Zhu R, Peng Y, et al. Tumor necrosis factor-alpha regulates photoreceptor cell autophagy after retinal detachment[J/OL]. Sci Rep, 2017, 7(1): 17108[2017-12-07]. https://pubmed.ncbi.nlm.nih.gov/29215050/. DOI: 10.1038/s41598-017-17400-3.
29. Choudhury S, Nashine S, Bhootada Y, et al. Modulation of the rate of retinal degeneration in T17M RHO mice by reprogramming the unfolded protein response[J]. Adv Exp Med Biol, 2014, 801: 455-462. DOI: 10.1007/978-1-4614-3209-8_58.
30. Al-Gayyar MM, Elsherbiny NM. Contribution of TNF-alpha to the development of retinal neurodegenerative disorders[J]. Eur Cytokine Netw, 2013, 24(1): 27-36. DOI: 10.1684/ecn.2013.0334.
31. Kauppinen A, Paterno JJ, Blasiak J, et al. Inflammation and its role in age-related macular degeneration[J]. Cell Mol Life Sci, 2016, 73(9): 1765-1786. DOI: 10.1007/s00018-016-2147-8.
32. 王蕾, 张晓敏, 李筱荣. 单核细胞趋化蛋白在视网膜疾病中的表达和作用[J]. 中华眼底病杂志, 2016, 32(5): 564-566. DOI: 10.3760/cma.j.issn.1005-1015.2016.05.032.Wang L, Zhang XM, Li XR. The status and progress of studies on monocyte chemoattractant protein-1 in retinal diseases[J]. Chin J Ocul Fundus Dis, 2016, 32(5): 564-566. DOI: 10.3760/cma.j.issn.1005-1015.2016.05.032.
33. Nakazawa T, Hisatomi T, Nakazawa C, et al. Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis[J]. Proc Natl Acad Sci USA, 2007, 104(7): 2425-2430. DOI: 10.1073/pnas.0608167104.
34. 刘舒. 抗血管内皮生长因子药物治疗湿性年龄相关性黄斑变性研究现状[J]. 中华实验眼科杂志, 2018, 36(12): 962-966. DOI: 10.3760/cma.j.issn.2095.0160.2018.12.014.Liu S. Research progress of anti-VEGF for the therapy in wet age-related macular degeneration[J]. Chin J Exp Ophthalmol, 2018, 36(12): 962-966. DOI: 10.3760/cma.j.issn.2095.0160.2018.12.014.
35. Maguire MG, Martin DF, Ying GS, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2016, 123(8): 1751-1761. DOI: 10.1016/j.ophtha.2016.03.045.
36. Miere A, Butori P, Cohen SY, et al. Vascular remodeling of choroidal neovascularization after anti-vascular endothelial growth factor therapy visualized on optical coherence tomography angiography[J]. Retina, 2019, 39(3): 548-557. DOI: 10.1097/IAE.0000000000001964.
37. Wright AF, Chakarova CF, Abd El-Aziz MM, et al. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait[J]. Nat Rev Genet, 2010, 11(4): 273-284. DOI: 10.1038/nrg2717.

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Advances in the mechanism of photoreceptor cell death induced by inflammation in age-related macular degeneration

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