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Table of Contents
Year : 2023  |  Volume : 5  |  Issue : 1  |  Page : 18

Insights into COVID-19 in age-related macular degeneration

Department of Internal Medicine, Medical School, Universidade Estadual Paulista, Botucatu, SP, Brazil

Date of Submission23-Dec-2022
Date of Decision19-Mar-2023
Date of Acceptance17-Apr-2023
Date of Web Publication11-May-2023

Correspondence Address:
Rogil Jose de Almeida Torres
Rua Emiliano Perneta 390, Conj. 1407, 80420-080 Curitiba, Parana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pajo.pajo_71_22

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Studies have shown that age-related macular degeneration (AMD) patients present a poor prognosis in coronavirus disease 2019 (COVID-19). These diseases have completely different etiologies and clinical courses. COVID-19 is a systemic, fast-evolving, and lethal infectious disease. AMD, in turn, is a chronic disease triggered by oxidative stress and is considered the main cause of irreversible blindness in old age. Both COVID-19 and AMD have in common the participation of immunological and inflammatory components arising from the imbalance of the redox state, responsible for the most severe phases of these diseases. Therefore, this study aims to present the triggering pathways of these diseases, as well as analyze the possible molecular mechanisms that increase the severity of COVID-19 in patients with AMD.

Keywords: Age-related macular degeneration, chemokines, coronavirus disease 2019, cytokines, inflammation, oxidative stress

How to cite this article:
de Almeida Torres RJ. Insights into COVID-19 in age-related macular degeneration. Pan Am J Ophthalmol 2023;5:18

How to cite this URL:
de Almeida Torres RJ. Insights into COVID-19 in age-related macular degeneration. Pan Am J Ophthalmol [serial online] 2023 [cited 2023 May 30];5:18. Available from: https://www.thepajo.org/text.asp?2023/5/1/18/376677

  Introduction Top

A retrospective study that analyzed 6,393 patients with COVID-19 found that 88 patients presented macular degeneration, and among these, the mortality rate was 25%. This mortality rate in patients with AMD was higher than in those with other comorbidities, such as type 2 diabetes mellitus (21%) and obesity (13.8%).[1] Corroborating these findings, a population-based nationwide cohort study in Korea (total n = 135,435) reported that patients with wet AMD (wAMD) were more susceptible to COVID-19, presenting a considerably higher risk of serious clinical outcomes.[2] Coronavirus disease 2019 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).[3],[4] It is an infectious disease with high morbidity,[5] and estimated fatality rate between 4% and 7%.[6] Preexisting conditions, such as old age, obesity, smoking, diabetes mellitus, cardiovascular disease, a change in coagulation status, and an impaired complement system, contribute to the development of severe COVID-19.[1],[7],[8],[9] These preexisting conditions that are related to the poor prognosis of COVID-19 are also related to the pathogenesis of AMD, the leading cause of irreversible blindness in old age.[10],[11],[12],[13]

The imbalance of the redox state, a determining factor for the advancement of COVID-19, activates important molecular pathways such as nuclear factor kappa B (NF-κB), receptor for advanced glycation end products (RAGE), and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, in the main effector cells of the innate and adaptive immune system, such as macrophages, monocytes, neutrophils, dendritic cells, natural killer (NK) cells, epithelial and endothelial cells.[14] The activation of these molecular pathways triggers the release of large amounts of pro-inflammatory cytokines and chemokines, such as interleukin (IL)-1 β, IL-2, IL-6, IL-7, IL-10, tumor necrosis alpha (TNF-α), interferon (IFN)-γ, C-C Motif Chemokine Ligand 2 (CCL2), CCL5, chemokine interferon-γ inducible protein 10 kDa (CXCL10), named cytokine storm. It is an acute, rapid and potentially lethal process responsible for acute respiratory distress syndrome.[14],[15],[16],[17],[18],[19]

In aging eyes, the imbalance of the redox state also activates the same molecular pathways (NF-κB, RAGE, and NLRP3 inflammasome)[20],[21],[22],[23],[24] inducing the slow and gradual release of the same cytokines. The release of pro-inflammatory cytokines causes chronic low-grade inflammation, leading AMD to its most advanced stages of geographic choroidal atrophy and/ or subretinal neovascularization.[25],[26],[27],[28],[29],[30] In this context, it is worth noting that the inflammatory mechanisms that facilitate the development of AMD, such as the aberrant innate immunity, also contribute to the development of severe COVID-19.[27],[30],[31],[32],[33],[34],[35],[36],[37],[38] Studies show that aging, a poor prognostic factor in COVID-19 and the main factor linked to AMD, causes an increase in plasma levels of inflammatory mediators, which may represent the critical point for the increased risk of multimorbidity and mortality in patients with AMD, who have been infected by SARS-CoV-2.[38] The same evolution has been observed in another serious viral disease, the human immunodeficiency virus (HIV), whose plasma levels of the inflammatory biomarkers C-reactive protein (CRP), IL-6, and CXCL10 were elevated in AMD patients and were associated with high mortality. This poor prognosis of HIV in AMD patients was attributed, at least in part, to systemic inflammation.[39]

Considering the worse prognosis of COVID-19 in patients with AMD relative to other serious comorbidities,[1],[2] this study aims to present the triggering pathways of these diseases, as well as analyze the possible molecular mechanisms that increase the severity of COVID-19 in patients with AMD.

  Coronavirus Disease 2019, “The Cytokine Storm” Top

SARS-CoV-2 is a single-stranded, enveloped RNA virus with the spike glycoprotein that can bind to serine protease, transmembrane serine protease 2 (TMPRSS2), and mainly to the angiotensin-converting enzyme 2 (ACE2) receptor, a master regulator of the renin-angiotensin system, to enter host cells.[40],[41] ACE2 is abundantly found in the type II pneumocytes of the lung alveolar epithelium, gastrointestinal tract, vascular endothelium, and other tissues.[42] This fact may explain the dysfunction of multiple organs and systems observed in its most severe clinical forms.[43],[44] After SARS-CoV-2 infection, reactive oxygen species (ROS) are overproduced as initiators of the toxic innate immune response against viruses.[45] The intense imbalance of the redox state triggers the activation of NF-κB, responsible for the release of IL-6, IL-1 β, TNF-α, and chemokines from immune and nonimmune cells.[14],[15],[46] The oxidative stress, as well as the activation of NF-κB, increases the expression of the NLRP3 inflammasome.[47],[48],[49] NLRP3 inflammasome activation leads to the production of IL-1 β/18, facilitating and perpetuating the formation of cytokine storm (IL-6/8/10/1RA, TNF-α, and CXCL10).[47] Oxidative stress also contributes to the exacerbation of cell hypoxia and can damage mitochondria in overwhelming amounts.[48],[50]

Among the main comorbidities that determine the poor prognosis of COVID-19, age, diabetes, obesity, and cardiovascular diseases play a central role. These comorbidities can accelerate the formation of advanced glycation end products (AGEs).[51] The interaction of AGEs with their RAGE receptor, expressed mainly on the surface of type one and type two alveolar epithelial cells, as well as alveolar macrophages, induces the NF-κB-mediated inflammatory cascade. Activation of NF-κB leads to the production of inflammatory cytokines and chemokines, causing acute lung injury, increasing severity and mortality from COVID-19.[52],[53],[54] Besides, pro-inflammatory cytokines and the production of reactive oxygen and nitrogen intermediates, respectively, may lead to endothelial dysfunction and hypercoagulation, worsening the patient's clinical condition.[55],[56]

In short, the resolution of the infection is directly linked to ROS overproduction and immune response; however, it can also result in immunopathogenesis and consequent worsening of the inflammatory condition. This condition is clinically expressed as a reduction in viral load that coincides with an increase in disease severity.[57],[58]

  Age-Related Macular Degeneration, “The Cytokine Drizzle” Top

As in COVID-19, the imbalance of the redox state imbalance has been considered the main factor that triggers and perpetuates AMD.[59] Such imbalance results in the oxidation of important biomolecules (lipids, proteins, carbohydrates, and deoxyribonucleic acid) that promote increased expression of toxic molecules such as malondialdehyde (MDA), carboxyethylpyrrole, AGEs, 4-hydroxynonenal, and 8-Hydroxy-2'-deoxyguanosine.[60] This excessive production of ROS, responsible for the increased expression of toxic molecules, induces mitochondrial dysfunction and ends up resulting in the accumulation of lipofuscin in RPE cells.[61],[62] This lipofuscin accumulation induces the dysfunction of RPE cells and causes a defective degradation of products derived from the phagocytosis of the outer segments of photoreceptor cells, inducing pathological accumulation of lipids in Bruch membrane (BM), giving rise to the drusen and other extracellular deposits.[63],[64] The drusen contain immunological and inflammatory markers such as serum amyloid P component, apolipoprotein E, immunoglobulin light chains, Factor X, prothrombin, and complement proteins (C3a, C5a, and C5b-9 complex), CRP, vitronectin, ubiquitin, integrins, and AGEs,[65],[66],[67],[68],[69] closely related to the activation of NLRP3 inflammasome and NF-κB.[70],[71],[72],[73] Besides the choriocapillaris, the RPE cells and photoreceptors also present inflammatory and immunological markers such as renin-angiotensin system (including ACE2/Ang1-7), Factor X, fibrinogen, immunoglobulin, human leukocyte antigen-DR isotype (HLA-DR), amyloid A component, apolipoprotein B/E, CRP, CCL5, CCL2, complement C3, C5, prothrombin, ubiquitin, AGEs, and vascular endothelial growth factor (VEGF).[60],[74],[75],[76],[77],[78],[79],[80],[81] It is important to point out that RPE cells also express a series of necessary cytokine receptors such as IL-1R,-4R,-6R,-8RA,-10RB, and IFN-AR1, indicating the sensitivity to systemic and retinal inflammatory signals.[31] In addition, the sensory retina has microglial cells, immune cells that, in response to the inflammatory stimuli, secrete molecules such as proteinases, nitric oxide, reactive oxygen intermediates, and pro-inflammatory cytokines, including IL-1 β, IL-6, and TNF-α.[82],[83],[84] In the AMD process, complement factor H is overexpressed in RPE cells,[85] being upregulated by IFNs.[86] Elevated levels of inflammation-related chemokines, including CXCL10, CCL14, CXCL16, CXCL7, and CCL22, were also found in the aqueous humor of AMD patients. CXC-chemokine ligand 10 and CCL22 were more elevated in eyes with recurrent wet AMD than in treatment-naive eyes. CXC-chemokine ligand 16 was positively correlated with lesion size. The increase in CCL22 was correlated with the OCT images that showed intraretinal fluid or hyperreflective foci.[87] Other studies have reported increased levels of CXCL10 as well as concentrations of CCL2, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and VEGF in the aqueous humor of patients with wet AMD.[88],[89] Studies have shown that the pro-inflammatory cytokine IL-1 β is responsible for the damage of the outer segments and the death of rods as well as for the increased expression in the patients' vitreous affected by polypoidal choroidal vasculopathy.[90],[91],[92]

These findings support the current understanding that inflammation plays a critical regulatory role in AMD. It often exacerbates oxidative stress, creating a self-perpetuating, vicious cycle of oxidation and inflammation, aggravating AMD.[93],[94],[95],[96] One of the means to perpetuate this cycle is the activation of the NF-κβ, involved in the regulation of gene expression associated with the immune and inflammatory responses.[25],[97]

  Age-Related Macular Degeneration, “A Systemic Inflammation” Top

Immune and inflammatory markers are not just upregulated within the eyeball. Genetic studies have mapped genes in the complement pathway that are involved in the regulation of innate immunity with AMD susceptibility.[31] Similarly, the association of RAGE gene polymorphisms with AMD has already been observed.[98] In addition, the frequencies of IFN-γ-and IL-17-expressing CD4+ T cells, as well as the levels of IFN-γ and IL-17 expression by CD4+ T cells, were shown to be significantly up-regulated in patients with AMD.[27] The same occurs with the serum levels of IFN beta.[99] Studies analyzing the serum of AMD patients reported elevated levels of proinflammatory cytokines IL-1α, IL-1 β, IL-4, IL-5, IL-10, IL-13, and IL-17, as well as altered expression levels of other inflammatory factors such as CRP, IL-6, and other cardiovascular biomarkers.[32],[34],[36],[100],[101] In parallel, altered phenotype and immune cell functions were observed in peripheral blood leukocytes in patients with AMD.[33] Corroborating this study, CCR1 and CCR2 were found to be upregulated in CD14 + CD16 + monocytes in patients with neovascular AMD.[30] Similarly, plasma levels of CCL5 were found to be upregulated in participants with GA.[102] It is important to note that CCL5/CCR5 could attract T-cells to release inflammatory factors and worsen the inflammatory damage.[103] Another study reported that serum eotaxin and CXCL10 levels were significantly elevated in all stages of AMD, except for eotaxin levels in neovascular AMD.[36] While eotaxin (a Th2-associated chemokine that participates in innate immunity) is a potent chemoattractant for eosinophils, CXCL10 has a high affinity for C-X-C Motif Chemokine Receptor 3 (CXCR3) found in activated T cells and NK cells.[104],[105] Both eotaxin and CXCL10 could serve as biomarkers to predict the early onset of AMD.[36] Multivariate logistic regression analyses demonstrated significant associations of urinary transforming growth factor-beta 1 levels and CCL2 levels in early AMD, as well as CCL2 levels with GA.[106]

  Discussion Top

“Inflammaging” versus coronavirus disease 2019 versus age-related macular degeneration

A relevant question may be raised: what mostly influenced the increase in COVID-19 mortality among AMD patients, old age, or AMD per se? This is a difficult question to answer. Initially, studies that demonstrated elevated systemic levels of inflammatory cytokines and chemokines in patients with AMD were compared with participants aged 60 years and older without AMD (control group).[27],[32],[34],[35],[99],[100],[101],[102],[106] This fact indicates that AMD can be related to the increase of systemic inflammatory markers. In Ramlall's study, patients with macular degeneration had a greater risk of severe COVID-19 clinical outcomes. This study attributed failures of the complement system to adverse outcomes.[1] It is important to note that dysregulation of complement cascades is a common feature of both AMD and COVID-19.[31],[107] However, this study involved a relatively small number of total patients and macular degeneration patients and did not adjust for confounders, including the known systemic risk factors for AMD. On the other hand, Yang's study, which involved a larger number of participants than Ramllal' 's, performed meticulous matches and adjustments to minimize the confounding effect for known COVID-19 risk factors such as age, sex, history of diabetes, and cardiovascular diseases. Yang et al. found an increased risk of susceptibility to severe clinical outcomes of COVID-19 in patients with wet AMD.[2]

Successful aging in adults is associated with low levels of inflammation. On the other hand, inflammation is a marker of biological aging, multimorbidity, and mortality risk.[38] Aging, and the consequent accumulation of senescent cells, is related to the progressive increase of a sterile, low-grade chronic inflammation, called inflammaging.[108],[109] Senescent cells activate NF-kB and RAGE signaling, stimulating the secretion of inflammatory cytokines, chemokines, and growth factors that contribute to inflammation.[110],[111],[112] Molecular changes related to the aging process, particularly pre-existing inflammatory conditions such as AMD, can exacerbate the morbidity and mortality associated with COVID-19.[113],[114],[115] On the other hand, systemic viral infections such as COVID-19 may be a trigger of cellular senescence, responsible for accelerating age-related diseases,[116],[117],[118] and can potentially trigger or worsen AMD. This possibility should be considered, as the ACE2 receptor can be found on retinal vascular endothelial, photoreceptor and RPE cells, as well as in the choroid. As such, SARS-CoV-2 can enter these cells, increase oxidative stress, and induce some degree of inflammation, basic conditions for triggering AMD.[40],[41],[74],[75] In addition, COVID-19 promotes an increase in the plasma levels of eotaxin-1, which is closely linked to neuroinflammation and neurodegenerative disorders, also likely to trigger or worsen AMD.[36],[119] [Figure 1] illustrates the interactions between age, inflammaging, severe COVID-19, and AMD.
Figure 1: Interactions between age, inflammaging, severe COVID-19, and AMD. AMD: Age-related macular degeneration, COVID-19: Coronavirus disease 2019

Click here to view

  Conclusion Top

COVID-19 is still a little understood condition, and different molecular mechanisms that are part of its pathogenesis are likely to be disclosed. Similarly, AMD's pathogenesis is not widely known. Nevertheless, several studies consistently report that COVID-19 and AMD are diseases characterized by an imbalance in the redox state that triggers immune and inflammatory changes. In both diseases, there is the activation of important and interconnected molecular pathways, such as NF-κB and NLRP3- inflammasome, and the interaction between AGE-RAGE. In COVID-19, the activation of these molecular pathways causes extreme systemic oxidative and inflammatory phenomena, leading to loss of life. In AMD, in turn, activation of these molecular pathways causes low-grade inflammation in the RPE/BM complex leading to vision loss. Several inflammatory mediators, including complement components, chemokines, and cytokines, are elevated at systemic levels in AMD and can significantly contribute to a poor prognosis in COVID-19 patients. Additional studies are expected and recommended to confirm the association of severe COVID-19 outcomes in patients with AMD. On the other hand, the possibility of premature triggering or worsening of AMD in patients who contracted COVID-19 are doubt that future epidemiological studies will clarify.

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Conflicts of interest

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  References Top

Ramlall V, Thangaraj PM, Meydan C, Foox J, Butler D, Kim J, et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med 2020;26:1609-15.  Back to cited text no. 1
Yang JM, Moon SY, Lee JY, Agalliu D, Yon DK, Lee SW. COVID-19 morbidity and severity in patients with age-related macular degeneration: A Korean nationwide cohort study. Am J Ophthalmol 2022;239:159-69.  Back to cited text no. 2
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33.  Back to cited text no. 3
Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol 2020;215:108427.  Back to cited text no. 4
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.  Back to cited text no. 5
Baud D, Qi X, Nielsen-Saines K, Musso D, Pomar L, Favre G. Real estimates of mortality following COVID-19 infection. Lancet Infect Dis 2020;20:773.  Back to cited text no. 6
Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: A review. JAMA Cardiol 2020;5:831-40.  Back to cited text no. 7
Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430-6.  Back to cited text no. 8
Gupta AK, Nethan ST, Mehrotra R. Tobacco use as a well-recognized cause of severe COVID-19 manifestations. Respir Med 2021;176:106233.  Back to cited text no. 9
Hyman L, Schachat AP, He Q, Leske MC. Hypertension, cardiovascular disease, and age-related macular degeneration. Age-related macular degeneration risk factors study group. Arch Ophthalmol 2000;118:351-8.  Back to cited text no. 10
Guymer RH, Chong EW. Modifiable risk factors for age-related macular degeneration. Med J Aust 2006;184:455-8.  Back to cited text no. 11
Chen X, Rong SS, Xu Q, Tang FY, Liu Y, Gu H, et al. Diabetes mellitus and risk of age-related macular degeneration: A systematic review and meta-analysis. PLoS One 2014;9:e108196.  Back to cited text no. 12
Torres RJ, Torres RJ, Luchini A, Ferreira AL. The oxidative and inflammatory nature of age-related macular degeneration. J Clin Ophthalmol Res 2022;10:3-8.  Back to cited text no. 13
Wang J, Jiang M, Chen X, Montaner LJ. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. J Leukoc Biol 2020;108:17-41.  Back to cited text no. 14
de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: Recent insights into emerging coronaviruses. Nat Rev Microbiol 2016;14:523-34.  Back to cited text no. 15
Shirato K, Kizaki T. SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages. Heliyon 2021;7:e06187.  Back to cited text no. 16
Patterson BK, Seethamraju H, Dhody K, Corley MJ, Kazempour K, Lalezari JP, et al. Disruption of the CCL5/RANTES-CCR5 pathway restores immune homeostasis and reduces plasma viral load in critical COVID-19. medRxiv 2020. doi: 10.1101/2020.05.02.20084673.  Back to cited text no. 17
Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – An update on the status. Mil Med Res 2020;7:11.  Back to cited text no. 18
Tang NL, Chan PK, Wong CK, To KF, Wu AK, Sung YM, et al. Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin Chem 2005;51:2333-40.  Back to cited text no. 19
Niazi S, Krogh Nielsen M, Sørensen TL, Subhi Y. Neutrophil-to-lymphocyte ratio in age-related macular degeneration: A systematic review and meta-analysis. Acta Ophthalmol 2019;97:558-66.  Back to cited text no. 20
Tan W, Zou J, Yoshida S, Jiang B, Zhou Y. The role of inflammation in age-related macular degeneration. Int J Biol Sci 2020;16:2989-3001.  Back to cited text no. 21
Penfold PL, Liew SC, Madigan MC, Provis JM. Modulation of major histocompatibility complex class II expression in retinas with age-related macular degeneration. Invest Ophthalmol Vis Sci 1997;38:2125-33.  Back to cited text no. 22
Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol 2013;13:438-51.  Back to cited text no. 23
Cousins SW, Espinosa-Heidmann DG, Csaky KG. Monocyte activation in patients with age-related macular degeneration: A biomarker of risk for choroidal neovascularization? Arch Ophthalmol 2004;122:1013-8.  Back to cited text no. 24
Torres RJ, Torres R, Luchini A, Ferreira AL. Transcription factor NF-κβ and molecules derived from its activation in age-related macular degeneration. Integr J Med Sci 2021;30:8.  Back to cited text no. 25
Spindler J, Zandi S, Pfister IB, Gerhardt C, Garweg JG. Cytokine profiles in the aqueous humor and serum of patients with dry and treated wet age-related macular degeneration. PLoS One 2018;13:e0203337.  Back to cited text no. 26
Chen J, Wang W, Li Q. Increased Th1/Th17 responses contribute to low-grade inflammation in age-related macular degeneration. Cell Physiol Biochem 2017;44:357-67.  Back to cited text no. 27
Schwarzer P, Kokona D, Ebneter A, Zinkernagel MS. Effect of inhibition of colony-stimulating factor 1 receptor on choroidal neovascularization in mice. Am J Pathol 2020;190:412-25.  Back to cited text no. 28
Leung KW, Barnstable CJ, Tombran-Tink J. Bacterial endotoxin activates retinal pigment epithelial cells and induces their degeneration through IL-6 and IL-8 autocrine signaling. Mol Immunol 2009;46:1374-86.  Back to cited text no. 29
Grunin M, Burstyn-Cohen T, Hagbi-Levi S, Peled A, Chowers I. Chemokine receptor expression in peripheral blood monocytes from patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2012;53:5292-300.  Back to cited text no. 30
Tuo J, Grob S, Zhang K, Chan CC. Genetics of immunological and inflammatory components in age-related macular degeneration. Ocul Immunol Inflamm 2012;20:27-36.  Back to cited text no. 31
Nassar K, Grisanti S, Elfar E, Lüke J, Lüke M, Grisanti S. Serum cytokines as biomarkers for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2015;253:699-704.  Back to cited text no. 32
Falk MK, Singh A, Faber C, Nissen MH, Hviid T, Sørensen TL. Dysregulation of CXCR3 expression on peripheral blood leukocytes in patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2014;55:4050-6.  Back to cited text no. 33
Seddon JM, George S, Rosner B, Rifai N. Progression of age-related macular degeneration: Prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol 2005;123:774-82.  Back to cited text no. 34
Krogh Nielsen M, Subhi Y, Molbech CR, Falk MK, Nissen MH, Sørensen TL. Systemic levels of interleukin-6 correlate with progression rate of geographic atrophy secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci 2019;60:202-8.  Back to cited text no. 35
Mo FM, Proia AD, Johnson WH, Cyr D, Lashkari K. Interferon gamma-inducible protein-10 (IP-10) and eotaxin as biomarkers in age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:4226-36.  Back to cited text no. 36
Jager MJ, Seddon JM. Eye diseases direct interest to complement pathway and macrophages as regulators of inflammation in COVID-19. Asia Pac J Ophthalmol (Phila) 2020;10:114-20.  Back to cited text no. 37
Teissier T, Boulanger E, Cox LS. Interconnections between inflammageing and immunosenescence during ageing. Cells 2022;11:359.  Back to cited text no. 38
Jabs DA, Van Natta ML, Trang G, Jones NG, Milush JM, Cheu R, et al. Association of age-related macular degeneration with mortality in patients with acquired immunodeficiency syndrome; role of systemic inflammation. Am J Ophthalmol 2019;199:230-7.  Back to cited text no. 39
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.  Back to cited text no. 40
Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020;126:1456-74.  Back to cited text no. 41
Spihlman AP, Gadi N, Wu SC, Moulton VR. COVID-19 and systemic lupus erythematosus: Focus on immune response and therapeutics. Front Immunol 2020;11:589474.  Back to cited text no. 42
Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020;26:1017-32.  Back to cited text no. 43
Li H, Liu L, Zhang D, Xu J, Dai H, Tang N, et al. SARS-CoV-2 and viral sepsis: Observations and hypotheses. Lancet 2020;395:1517-20.  Back to cited text no. 44
Wang H, Qin R, Zhang J, Chen Y. Possible immunity, inflammation, and oxidative stress mechanisms of Alzheimer's disease in COVID-19 patients. Clin Neurol Neurosurg 2021;201:106414.  Back to cited text no. 45
Kozlov EM, Ivanova E, Grechko AV, Wu WK, Starodubova AV, Orekhov AN. Involvement of oxidative stress and the innate immune system in SARS-CoV-2 infection. Diseases 2021;9:17.  Back to cited text no. 46
Zhao N, Di B, Xu LL. The NLRP3 inflammasome and COVID-19: Activation, pathogenesis and therapeutic strategies. Cytokine Growth Factor Rev 2021;61:2-15.  Back to cited text no. 47
Cecchini R, Cecchini AL. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypotheses 2020;143:110102.  Back to cited text no. 48
Weber AN, Bittner ZA, Shankar S, Liu X, Chang TH, Jin T, et al. Recent insights into the regulatory networks of NLRP3 inflammasome activation. J Cell Sci 2020;133:jcs248344.  Back to cited text no. 49
Saleh J, Peyssonnaux C, Singh KK, Edeas M. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion 2020;54:1-7.  Back to cited text no. 50
Sellegounder D, Zafari P, Rajabinejad M, Taghadosi M, Kapahi P. Advanced glycation end products (AGEs) and its receptor, RAGE, modulate age-dependent COVID-19 morbidity and mortality. A review and hypothesis. Int Immunopharmacol 2021;98:107806.  Back to cited text no. 51
Kerkeni M, Gharbi J. RAGE receptor: May be a potential inflammatory mediator for SARS-COV-2 infection? Med Hypotheses 2020;144:109950.  Back to cited text no. 52
Rojas A, Gonzalez I, Morales MA. SARS-CoV-2-mediated inflammatory response in lungs: Should we look at RAGE? Inflamm Res 2020;69:641-3.  Back to cited text no. 53
Feng Z, Zhu L, Wu J. RAGE signalling in obesity and diabetes: Focus on the adipose tissue macrophage. Adipocyte 2020;9:563-6.  Back to cited text no. 54
Rhee SY, Kim YS. The role of advanced glycation end products in diabetic vascular complications. Diabetes Metab J 2018;42:188-95.  Back to cited text no. 55
Wu H, Li R, Pei LG, Wei ZH, Kang LN, Wang L, et al. Emerging role of high mobility group box-1 in thrombosis-related diseases. Cell Physiol Biochem 2018;47:1319-37.  Back to cited text no. 56
Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet 2003;361:1767-72.  Back to cited text no. 57
Wang WK, Chen SY, Liu IJ, Kao CL, Chen HL, Chiang BL, et al. Temporal relationship of viral load, ribavirin, interleukin (IL)-6, IL-8, and clinical progression in patients with severe acute respiratory syndrome. Clin Infect Dis 2004;39:1071-5.  Back to cited text no. 58
Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000;45:115-34.  Back to cited text no. 59
Torres RJ, Luchini A, Torres RJ, Ferreira LA. Potential molecular biomarkers of oxidative stress in age related macular degeneration. New Front Ophthalmol 2021;7:1-11.  Back to cited text no. 60
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 2014;94:909-50.  Back to cited text no. 61
Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, et al. Drusen proteome analysis: An approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci U S A 2002;99:14682-7.  Back to cited text no. 62
Mammadzada P, Corredoira PM, André H. The role of hypoxia-inducible factors in neovascular age-related macular degeneration: A gene therapy perspective. Cell Mol Life Sci 2020;77:819-33.  Back to cited text no. 63
Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 1997;37:3483-93.  Back to cited text no. 64
Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. 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. Prog Retin Eye Res 2001;20:705-32.  Back to cited text no. 65
Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000;14:835-46.  Back to cited text no. 66
Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A 2006;103:2328-33.  Back to cited text no. 67
Nagineni CN, Samuel W, Nagineni S, Pardhasaradhi K, Wiggert B, Detrick B, et al. Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: Involvement of mitogen-activated protein kinases. J Cell Physiol 2003;197:453-62.  Back to cited text no. 68
Farboud B, Aotaki-Keen A, Miyata T, Hjelmeland LM, Handa JT. Development of a polyclonal antibody with broad epitope specificity for advanced glycation endproducts and localization of these epitopes in Bruch's membrane of the aging eye. Mol Vis 1999;5:11.  Back to cited text no. 69
Doyle SL, Campbell M, Ozaki E, Salomon RG, Mori A, Kenna PF, et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med 2012;18:791-8.  Back to cited text no. 70
Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Köhl J, et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 2013;122:3473-81.  Back to cited text no. 71
Liu RT, Gao J, Cao S, Sandhu N, Cui JZ, Chou CL, et al. Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: Implications for inflammasome activation in age-related macular degeneration. Invest Ophthalmol Vis Sci 2013;54:2225-37.  Back to cited text no. 72
Xie J, Méndez JD, Méndez-Valenzuela V, Aguilar-Hernández MM. Cellular signalling of the receptor for advanced glycation end products (RAGE). Cell Signal 2013;25:2185-97.  Back to cited text no. 73
Choudhary R, Kapoor MS, Singh A, Bodakhe SH. Therapeutic targets of renin-angiotensin system in ocular disorders. J Curr Ophthalmol 2017;29:7-16.  Back to cited text no. 74
Nagai N, Oike Y, Izumi-Nagai K, Urano T, Kubota Y, Noda K, et al. Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization. Arterioscler Thromb Vasc Biol 2006;26:2252-9.  Back to cited text no. 75
Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 2001;20:385-414.  Back to cited text no. 76
Holtkamp GM, Kijlstra A, Peek R, de Vos AF. Retinal pigment epithelium-immune system interactions: Cytokine production and cytokine-induced changes. Prog Retin Eye Res 2001;20:29-48.  Back to cited text no. 77
Loeffler KU, Mangini NJ. Immunolocalization of ubiquitin and related enzymes in human retina and retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol 1997;235:248-54.  Back to cited text no. 78
Crane IJ, Kuppner MC, McKillop-Smith S, Knott RM, Forrester JV. Cytokine regulation of RANTES production by human retinal pigment epithelial cells. Cell Immunol 1998;184:37-44.  Back to cited text no. 79
Pons M, Marin-Castaño ME. Cigarette smoke-related hydroquinone dysregulates MCP-1, VEGF and PEDF expression in retinal pigment epithelium in vitro and in vivo. PLoS One 2011;6:e16722.  Back to cited text no. 80
Lueck K, Wasmuth S, Williams J, Hughes TR, Morgan BP, Lommatzsch A, et al. Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration. Eye (Lond) 2011;25:1074-82.  Back to cited text no. 81
Karlstetter M, Ebert S, Langmann T. Microglia in the healthy and degenerating retina: Insights from novel mouse models. Immunobiology 2010;215:685-91.  Back to cited text no. 82
Welser-Alves JV, Milner R. Microglia are the major source of TNF-α and TGF-β1 in postnatal glial cultures; regulation by cytokines, lipopolysaccharide, and vitronectin. Neurochem Int 2013;63:47-53.  Back to cited text no. 83
Natoli R, Fernando N, Madigan M, Chu-Tan JA, Valter K, Provis J, et al. Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration. Mol Neurodegener 2017;12:31.  Back to cited text no. 84
Parmeggiani F, Sorrentino FS, Romano MR, Costagliola C, Semeraro F, Incorvaia C, et al. Mechanism of inflammation in age-related macular degeneration: An up-to-date on genetic landmarks. Mediators Inflamm 2013;2013:435607.  Back to cited text no. 85
Kim YH, He S, Kase S, Kitamura M, Ryan SJ, Hinton DR. Regulated secretion of complement factor H by RPE and its role in RPE migration. Graefes Arch Clin Exp Ophthalmol 2009;247:651-9.  Back to cited text no. 86
Liu F, Ding X, Yang Y, Li J, Tang M, Yuan M, et al. Aqueous humor cytokine profiling in patients with wet AMD. Mol Vis 2016;22:352-61.  Back to cited text no. 87
Agawa T, Usui Y, Wakabayashi Y, Okunuki Y, Juan M, Umazume K, et al. Profile of intraocular immune mediators in patients with age-related macular degeneration and the effect of intravitreal bevacizumab injection. Retina 2014;34:1811-8.  Back to cited text no. 88
Jonas JB, Tao Y, Neumaier M, Findeisen P. Monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in exudative age-related macular degeneration. Arch Ophthalmol 2010;128:1281-6.  Back to cited text no. 89
Zhao M, Bai Y, Xie W, Shi X, Li F, Yang F, et al. Interleukin-1β level is increased in vitreous of patients with Neovascular Age-Related Macular Degeneration (nAMD) and Polypoidal Choroidal Vasculopathy (PCV). PLoS One 2015;10:e0125150.  Back to cited text no. 90
Hu SJ, Calippe B, Lavalette S, Roubeix C, Montassar F, Housset M, et al. Upregulation of P2RX7 in Cx3cr1-deficient mononuclear phagocytes leads to increased interleukin-1β secretion and photoreceptor Neurodegeneration. J Neurosci 2015;35:6987-96.  Back to cited text no. 91
Charles-Messance H, Blot G, Couturier A, Vignaud L, Touhami S, Beguier F, et al. IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis. J Neuroinflammation 2020;17:1.  Back to cited text no. 92
Planck SR, Dang TT, Graves D, Tara D, Ansel JC, Rosenbaum JT. Retinal pigment epithelial cells secrete interleukin-6 in response to interleukin-1. Invest Ophthalmol Vis Sci 1992;33:78-82.  Back to cited text no. 93
Tsutsumi C, Sonoda KH, Egashira K, Qiao H, Hisatomi T, Nakao S, et al. The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization. J Leukoc Biol 2003;74:25-32.  Back to cited text no. 94
Rahman I, Antonicelli F, MacNee W. Molecular mechanism of the regulation of glutathione synthesis by tumor necrosis factor-alpha and dexamethasone in human alveolar epithelial cells. J Biol Chem 1999;274:5088-96.  Back to cited text no. 95
Bakin AV, Stourman NV, Sekhar KR, Rinehart C, Yan X, Meredith MJ, et al. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding phase II detoxifying proteins. Free Radic Biol Med 2005;38:375-87.  Back to cited text no. 96
Barnes PJ, Karin M. Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066-71.  Back to cited text no. 97
Banevicius M, Vilkeviciute A, Kriauciuniene L, Liutkeviciene R, Deltuva VP. The association between variants of Receptor for Advanced Glycation End products (RAGE) gene polymorphisms and age-related macular degeneration. Med Sci Monit 2018;24:190-9.  Back to cited text no. 98
Afarid M, Azimi A, Malekzadeh M. Evaluation of serum interferons in patients with age-related macular degeneration. J Res Med Sci 2019;24:24.  Back to cited text no. 99
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Subhi Y, Krogh Nielsen M, Molbech CR, Oishi A, Singh A, Nissen MH, et al. Plasma markers of chronic low-grade inflammation in polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. Acta Ophthalmol 2019;97:99-106.  Back to cited text no. 100
Mitta VP, Christen WG, Glynn RJ, Semba RD, Ridker PM, Rimm EB, et al. C-reactive protein and the incidence of macular degeneration: Pooled analysis of 5 cohorts. JAMA Ophthalmol 2013;131:507-13.  Back to cited text no. 101
Krogh Nielsen M, Subhi Y, Molbech CR, Falk MK, Nissen MH, Sørensen TL. Chemokine profile and the alterations in CCR5-CCL5 axis in geographic atrophy secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci 2020;61:28.  Back to cited text no. 102
Jones KL, Maguire JJ, Davenport AP. Chemokine receptor CCR5: From AIDS to atherosclerosis. Br J Pharmacol 2011;162:1453-69.  Back to cited text no. 103
Luster AD. Chemokines – Chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338:436-45.  Back to cited text no. 104
Robertson MJ. Role of chemokines in the biology of natural killer cells. J Leukoc Biol 2002;71:173-83.  Back to cited text no. 105
Guymer RH, Tao LW, Goh JK, Liew D, Ischenko O, Robman LD, et al. Identification of urinary biomarkers for age-related macular degeneration. Invest Ophthalmol Vis Sci 2011;52:4639-44.  Back to cited text no. 106
Risitano AM, Mastellos DC, Huber-Lang M, Yancopoulou D, Garlanda C, Ciceri F, et al. Complement as a target in COVID-19? Nat Rev Immunol 2020;20:343-4.  Back to cited text no. 107
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244-54.  Back to cited text no. 108
Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: Causes and consequences. Trends Mol Med 2010;16:238-46.  Back to cited text no. 109
Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 2012;24:835-45.  Back to cited text no. 110
Ryder JR, Northrop E, Rudser KD, Kelly AS, Gao Z, Khoury PR, et al. Accelerated early vascular aging among adolescents with obesity and/or type 2 diabetes mellitus. J Am Heart Assoc 2020;9:e014891.  Back to cited text no. 111
Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol 2010;5:99-118.  Back to cited text no. 112
Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LF. The trinity of COVID-19: Immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363-74.  Back to cited text no. 113
Nehme J, Borghesan M, Mackedenski S, Bird TG, Demaria M. Cellular senescence as a potential mediator of COVID-19 severity in the elderly. Aging Cell 2020;19:e13237.  Back to cited text no. 114
Sargiacomo C, Sotgia F, Lisanti MP. COVID-19 and chronological aging: Senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? Aging (Albany NY) 2020;12:6511-7.  Back to cited text no. 115
Chuprin A, Gal H, Biron-Shental T, Biran A, Amiel A, Rozenblatt S, et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev 2013;27:2356-66.  Back to cited text no. 116
Kohli J, Veenstra I, Demaria M. The struggle of a good friend getting old: Cellular senescence in viral responses and therapy. EMBO Rep 2021;22:e52243.  Back to cited text no. 117
McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol 2018;217:65-77.  Back to cited text no. 118
Nazarinia D, Behzadifard M, Gholampour J, Karimi R, Gholampour M. Eotaxin-1 (CCL11) in neuroinflammatory disorders and possible role in COVID-19 neurologic complications. Acta Neurol Belg 2022;122:865-9.  Back to cited text no. 119


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