Role of inflammatory aging in the development of age-related macular degeneration
DOI: 10.32364/2311-7729-2024-24-3-5
A.S. Khalatyan, Yu. Yusef
M.M. Krasnov Research Institute of Eye Diseases, Moscow, Russian Federation
Aging is often accompanied by systemic inflammation known as ‘inflamm-aging'. This process is characterized by an increase in proinflammatory cytokines and a decrease in anti-inflammatory cytokines. Inflammatory aging is caused by both chronic subclinical inflammation from exogenous factors and intrinsic inflammatory processes associated with progressive mitochondrial degeneration. Age-related macular degeneration (AMD) is the primary cause of blindness and visual impairment in patients over 60 years of age in developed countries. The disease has a complex pathogenesis, with inflammation playing a central role in the degenerative processes in both dry and wet AMD. The development of AMD involves various pro-inflammatory stimuli, cells, mediators, and metabolic pathways. The pathogenesis of AMD begins with the thickening of Bruch's membrane caused by the accumulation of lipids and proteins, resulting in the formation of subretinal deposits called drusen. These deposits impede fluid outflow from retinal pigment epithelium (RPE) cells through Bruch's membrane, leading to an increased metabolic burden on the RPE. This cellular stress triggers a pro-inflammatory cascade.
The purpose of this paper is to examine the current understanding of the role of inflammation in AMD and to explore potential new therapeutic approaches.
Keywords: aging, inflammation, age-related macular degeneration, inflammatory aging, antiangiogenic therapy.
For citation: Khalatyan A.S., Yusef Yu. Role of inflammatory aging in the development of age-related macular degeneration. Russian Journal of Clinical Ophthalmology. 2024;24(3):127–132 (in Russ.). DOI: 10.32364/2311-7729-2024-24-3-5.
About the authors:
Anait S. Khalatyan — C. Sc. (Med.), junior researcher of the Division of Retinal and Optic Nerve Disorders, M.M. Krasnov Research Institute of Eye Diseases; 11A, B, Rossolimo str., Moscow, 119021, Russian Federation; ORCID iD 0000-0001-6255-5544.
Yusef Yusef — Dr. Sc. (Med.), Professor, Head of the Division of Current Treatment Methods in Ophthalmology, Director, M.M. Krasnov Research Institute of Eye Diseases; 11A, B, Rossolimo str., Moscow, 119021, Russian Federation; ORCID iD 0000-0003-4043-456X.
Contact information: Anait S. Khalatyan, е-mail: anaits92@gmail.com.
Financial Disclosure: no authors have a financial or property interest in any material or method mentioned.
There is no conflict of interest.
Received 08.02.2024.
Revised 04.03.2024.
Accepted 27.03.2024.
References
1. Rozing M.P., Durhuus J.A., Krogh Nielsen M. et al. Age-related macular degeneration: A two-level model hypothesis. Prog Retin Eye Res. 2020;76:100825. DOI: 10.1016/j.preteyeres.2019.100825.
2. Colijn J.M., Buitendijk G.H.S., Prokofyeva E. et al. Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future. Ophthalmology. 2017;124(12):1753–1763. DOI: 10.1016/j.ophtha.2017.05.035.
3. Ambati J., Fowler B.J. Mechanisms of age-related macular degeneration. Neuron. 2012;75(1):26–39. DOI: 10.1016/j.neuron.2012.06.018.
4. Kirkwood T.B. Understanding the odd science of aging. Cell. 2005;120(4):437–447. DOI: 10.1016/j.cell.2005.01.027.
5. Mitchell G.F. Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol (1985). 2008;105(5):1652–1660. DOI: 10.1152/japplphysiol.90549.2008.
6. Hayflick L., Moorhead P.S. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621. DOI: 10.1016/0014-4827(61)90192-6.
7. McHugh D., Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol. 2018;217(1):65–77. DOI: 10.1083/jcb.201708092.
8. Park C.B., Larsson N.G. Mitochondrial DNA mutations in disease and aging. J Cell Biol. 2011;193(5):809–818. DOI: 10.1083/jcb.201010024.
9. López-Otín C., Blasco M.A., Partridge L. et al. The hallmarks of aging. Cell. 2013;153(6):1194–1217. DOI: 10.1016/j.cell.2013.05.039.
10. Luu J., Palczewski K. Human aging and disease: Lessons from age-related macular degeneration. Proc Natl Acad Sci U S A. 2018;115(12):2866–2872. DOI: 10.1073/pnas.1721033115.
11. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–435. DOI: 10.1038/nature07201.
12. Salminen A., Huuskonen J., Ojala J. et al. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev. 2008;7(2):83–105. DOI: 10.1016/j.arr.2007.09.002.
13. Adams A.A., Breathnach C.C., Katepalli M.P. et al. Advanced age in horses affects divisional history of T cells and inflammatory cytokine production. Mech Ageing Dev. 2008;129(11):656–664. DOI: 10.1016/j.mad.2008.09.004.
14. Ермакова Н.А. Роль воспаления в развитии возрастной макулярной дистрофии. Вестник офтальмологии. 2018;134(6):116–123.Ermakova N.A. The role of inflammation in Age-related Macular Degeneration. Vestn Oftalmol. 2018;134(6):116–123 (in Russ.). DOI: 10.17116/oftalma2018134061116.
15. Chen M., Xu H. Parainflammation, chronic inflammation, and age-related macular degeneration. J Leukoc Biol. 2015;98(5):713–725. DOI: 10.1189/jlb.3RI0615-239R.
16. Subhi Y., Krogh Nielsen M., Molbech C.R. et al. Plasma markers of chronic low-grade inflammation in polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. Acta Ophthalmol. 2019;97(1):99–106. DOI: 10.1111/aos.13886.
17. Handa J.T., Bowes Rickman C., Dick A.D. et al. A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration. Nat Commun. 2019;10(1):3347. DOI: 10.1038/s41467-019-11262-1.
18. Camino A., Guo Y., You Q. et al. Detecting and measuring areas of choriocapillaris low perfusion in intermediate, non-neovascular age-related macular degeneration. Neurophotonics. 2019;6(4):041108. DOI: 10.1117/1.NPh.6.4.041108.
19. Juel H.B., Faber C., Udsen M.S. et al. Chemokine expression in retinal pigment epithelial ARPE-19 cells in response to coculture with activated T cells. Invest Ophthalmol Vis Sci. 2012;53(13):8472–8480. DOI: 10.1167/iovs.12-9963.
20. Klettner A., Kaya L., Flach J. et al. Basal and apical regulation of VEGF-A and placenta growth factor in the RPE/choroid and primary RPE. Mol Vis. 2015;21:736–748. PMID: 26167115.
21. Ren J., Ren A., Deng X. et al. Long-Chain Polyunsaturated Fatty Acids and Their Metabolites Regulate Inflammation in Age-Related Macular Degeneration. J Inflamm Res. 2022;15:865–880. DOI: 10.2147/JIR.S347231.
22. Ban N., Lee T.J., Sene A. et al. Impaired monocyte cholesterol clearance initiates age-related retinal degeneration and vision loss. JCI Insight. 2018;3(17):e120824. DOI: 10.1172/jci.insight.120824.
23. Owsley C., McGwin G. Jr, Clark M.E. et al. Delayed Rod-Mediated Dark Adaptation Is a Functional Biomarker for Incident Early Age-Related Macular Degeneration. Ophthalmology. 2016;123(2):344–351. DOI: 10.1016/j.ophtha.2015.09.041.
24. Curcio C.A. Photoreceptor topography in ageing and age-related maculopathy. Eye (Lond). 2001;15(Pt 3):376–383. DOI: 10.1038/eye.2001.140.
25. Dunaief J.L., Dentchev T., Ying G.S., Milam A.H. The role of apoptosis in age-related macular degeneration. Arch Ophthalmol. 2002;120(11):1435–1442. DOI: 10.1001/archopht.120.11.1435.
26. Chen M., Xu H. Parainflammation, chronic inflammation, and age-related macular degeneration. J Leukoc Biol. 2015;98(5):713–725. DOI: 10.1189/jlb.3RI0615-239R.
27. Bhutto I., Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. Mol Aspects Med. 2012;33(4):295–317. DOI: 10.1016/j.mam.2012.04.005.
28. Yuan X., Gu X., Crabb J.S. et al. Quantitative proteomics: comparison of the macular Bruch membrane/choroid complex from age-related macular degeneration and normal eyes. Mol Cell Proteomics. 2010;9(6):1031–1046. DOI: 10.1074/mcp.M900523-MCP200.
29. Mullins R.F., Schoo D.P., Sohn E.H. et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol. 2014;184(11):3142–3153. DOI: 10.1016/j.ajpath.2014.07.017.
30. Doyle S.L., Campbell M., Ozaki E. et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med. 2012;18(5):791–798. DOI: 10.1038/nm.2717.
31. Kijlstra A., Berendschot T.T. Age-related macular degeneration: a complementopathy? Ophthalmic Res. 2015;54(2):64–73. DOI: 10.1159/000432401.
32. Chalam K.V., Grover S., Sambhav K. et al. Aqueous interleukin-6 levels are superior to vascular endothelial growth factor in predicting therapeutic response to bevacizumab in age-related macular degeneration. J Ophthalmol. 2014;2014:502174. DOI: 10.1155/2014/502174.
33. Lechner J., Chen M., Hogg R.E. et al. Peripheral blood mononuclear cells from neovascular age-related macular degeneration patients produce higher levels of chemokines CCL2 (MCP-1) and CXCL8 (IL-8). J Neuroinflammation. 2017;14(1):42. DOI: 10.1186/s12974-017-0820-y.
34. Norris G.T., Smirnov I., Filiano A.J. et al. Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury. J Exp Med. 2018;215(7):1789–1801. DOI: 10.1084/jem.20172244.
35. Subhi Y., Nielsen M.K., Molbech C.R. et al. T-cell differentiation and CD56+ levels in polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. Aging (Albany NY). 2017;9(11):2436–2452. DOI: 10.18632/aging.101329.
36. Yu Y., Bao Z., Wang X. et al. The G-Protein-Coupled Chemoattractant Receptor Fpr2 Exacerbates High Glucose-Mediated Proinflammatory Responses of Müller Glial Cells. Front Immunol. 2017;8:1852. DOI: 10.3389/fimmu.2017.01852.
37. Besser M., Jagatheaswaran M., Reinhard J. et al. Tenascin C regulates proliferation and differentiation processes during embryonic retinogenesis and modulates the de-differentiation capacity of Müller glia by influencing growth factor responsiveness and the extracellular matrix compartment. Dev Biol. 2012;369(2):163–176. DOI: 10.1016/j.ydbio.2012.05.020.
38. Reinhard J., Roll L., Faissner A. Tenascins in Retinal and Optic Nerve Neurodegeneration. Front Integr Neurosci. 2017;11:30. DOI: 10.3389/fnint.2017.00030.
39. Krogh Nielsen M., Subhi Y., Molbech C.R. et al. Systemic Levels of Interleukin-6 Correlate With Progression Rate of Geographic Atrophy Secondary to Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2019;60(1):202–208. DOI: 10.1167/iovs.18-25878.
40. Spindler J., Zandi S., Pfister I.B. et al. Cytokine profiles in the aqueous humor and serum of patients with dry and treated wet age-related macular degeneration. PLoS One. 2018;13(8):e0203337. DOI: 10.1371/journal.pone.0203337.
41. Ma Z., Liu J., Li J. et al. Klotho Levels are Decreased and Associated with Enhanced Oxidative Stress and Inflammation in the Aqueous Humor in Patients with Exudative Age-related Macular Degeneration. Ocul Immunol Inflamm. 2022;30(3):630–637. DOI: 10.1080/09273948.2020.1828488.
42. Arrigo A., Aragona E., Bandello F. The Role of Inflammation in Age-Related Macular Degeneration: Updates and Possible Therapeutic Approaches. Asia Pac J Ophthalmol (Phila). 2023;12(2):158–167. DOI: 10.1097/APO.0000000000000570.
43. Maruko I., Okada A.A., Iida T. et al. Brolucizumab-related intraocular inflammation in Japanese patients with age-related macular degeneration: a short-term multicenter study. Graefes Arch Clin Exp Ophthalmol. 2021;259(9):2857–2859. DOI: 10.1007/s00417-021-05136-w.
44. Enríquez A.B., Baumal C.R., Crane A.M. et al. Early Experience With Brolucizumab Treatment of Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2021;139(4):441–448. DOI: 10.1001/jamaophthalmol.2020.7085.
45. Bulirsch L.M., Saβmannshausen M., Nadal J. et al. Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study. Br J Ophthalmol. 2022;106(9):1288–1294. DOI: 10.1136/bjophthalmol-2020-318672.
46. Sharma A., Kumar N., Parachuri N. et al. Brolucizumab-related retinal vasculitis: emerging disconnect between clinical trials and real world. Eye (Lond). 2021;35(5):1292–1294. DOI: 10.1038/s41433-020-01227-w.
47. Pacinella G., Ciaccio A.M., Tuttolomondo A. Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases. Int J Mol Sci. 2022;23(24):15722. DOI: 10.3390/ijms232415722.
48. Sun J., Nie H., Pan P. et al. Combined Anti-Angiogenic and Anti-Inflammatory Nanoformulation for Effective Treatment of Ocular Vascular Diseases. Int J Nanomedicine. 2023;18:437–453. DOI: 10.2147/IJN.S387428.
49. Coll R.C., Hill J.R., Day C.J. et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol. 2019;15(6):556–559. DOI: 10.1038/s41589-019-0277-7.
50. Lee K.S., Lin S., Copland D.A. et al. Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration. J Neuroinflammation. 2021;18(1):32. DOI: 10.1186/s12974-021-02088-0.
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