Skip to main content
SpringerLink
Log in

Interrelation Between Oxidative Stress and Complement Activation in Models of Age-Related Macular Degeneration

  • Conference paper
  • First Online:
Retinal Degenerative Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 854))

Abstract

Millions of individuals older than 50-years suffer from age-related macular degeneration (AMD). Associated with this multifactorial disease are polymorphisms of complement factor genes and a main environmental risk factor—oxidative stress. Until now the linkage between these risk factors for AMD has not been fully understood. Recent studies, integrating results on oxidative stress, complement activation, epidemiology and ocular pathology suggested the following sequence in AMD-etiology: initially, chronic oxidative stress results in modification of proteins and lipids in the posterior of the eye; these tissue alterations trigger chronic inflammation, involving the complement system; and finally, invasive immune cells facilitate pathology in the retina. Here, we summarize the results for animal studies which aim to elucidate this molecular interplay of oxidative events and tissue-specific complement activation in the eye.

Luciana M. Pujol-Lereis and Nicole Schäfer both have contributed equally to the study.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Anderson DH, Radeke MJ, Gallo NB et al (2010) The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29:95–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beattie JR, Pawlak AM, Boulton ME et al (2010) Multiplex analysis of age-related protein and lipid modifications in human Bruch’s membrane. FASEB J 24:4816–4824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Begum R, Powner MB, Hudson N et al (2013) Treatment with 670 nm light up regulates cytochrome C oxidase expression and reduces inflammation in an age-related macular degeneration model. PLoS One 8:e57828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Birari R, Villegas L, Locke J et al (2012) Conditional knock down of SOD3 in smooth muscle cells augments chronic hypoxic pulmonary vascular remodeling and inflammation. Am J Respir Crit Care Med 185.1_MeetingAbstracts.A4742

    Google Scholar 

  • Bora NS, Gobleman CL, Atkinson JP et al (1993) Differential expression of the complement regulatory proteins in the human eye. Invest Ophthalmol Vis Sci 34:3579–3584

    CAS  PubMed  Google Scholar 

  • Coffey PJ, Gias C, McDermott CJ et al (2007) Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc Natl Acad Sci USA 104:16651–16656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cruz-Guilloty F, Saeed A, Echegaray J et al (2013) Infiltration of proinflammatory m1 macrophages into the outer retina precedes damage in a mouse model of age-related macular degeneration. Int J Inflam 2013:503725

    Article  PubMed  PubMed Central  Google Scholar 

  • Ebrahem Q, Renganathan K, Sears J et al (2006) Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: implications for age-related macular degeneration. Proc Natl Acad Sci U S A 103:13480–13484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faber C, Williams J, Juel HB et al (2012) Complement factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice. Invest Ophthalmol Vis Sci 53:6324–6330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hadziahmetovic M, Dentchev T, Song Y et al (2008) Ceruloplasmin/hephaestin knockout mice model morphologic and molecular features of AMD. Invest Ophthalmol Vis Sci 49:2728–2736

    Article  PubMed  PubMed Central  Google Scholar 

  • Hadziahmetovic M, Kumar U, Song Y et al (2012a) Microarray analysis of murine retinal light damage reveals changes in iron regulatory, complement, and antioxidant genes in the neurosensory retina and isolated RPE. Invest Ophthalmol Vis Sci 53:5231–5241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hadziahmetovic M, Pajic M, Grieco S et al (2012b) The oral iron chelator deferiprone protects against retinal degeneration induced through diverse mechanisms. Transl Vis Sci Technol 1:2

    Article  PubMed  PubMed Central  Google Scholar 

  • Hollyfield JG, Bonilha VL, Rayborn ME et al (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14:194–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imamura Y, Noda S, Hashizume K et al (2006) Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci U S A 103:11282–11287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joseph K, Kulik L, Coughlin B et al (2013) Oxidative stress sensitizes retinal pigmented epithelial (RPE) cells to complement-mediated injury in a natural antibody-, lectin pathway-, and phospholipid epitope-dependent manner. J Biol Chem 288:12753–12765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kew RR, Ghebrehiwet B, Janoff A (1985) Cigarette smoke can activate the alternative pathway of complement in vitro by modifying the third component of complement. J Clin Invest 75:1000–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan JC, Thurlby DA, Shahid H et al (2006) Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol 90:75–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao H, Seo SJ, Biswal MR et al (2014) Mitochondrial oxidative stress in the retinal pigment epithelium leads to localized retinal degeneration. Invest Ophthalmol Vis Sci 55:4613–4627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pickering MC, Cook HT, Warren J et al (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428

    CAS  PubMed  Google Scholar 

  • Pratt JR, Basheer SA, Sacks SH (2002) Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 8:582–587

    Article  CAS  PubMed  Google Scholar 

  • Radu RA, Hu J, Yuan Q et al (2011) Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for Stargardt macular degeneration. J Biol Chem 286:18593–18601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rohrer B, Guo Y, Kunchithapautham K et al (2007) Eliminating complement factor D reduces photoreceptor susceptibility to light-induced damage. Invest Ophthalmol Vis Sci 48:5282–5289

    Article  PubMed  Google Scholar 

  • Rutar M, Natoli R, Kozulin P et al (2011) Analysis of complement expression in light-induced retinal degeneration: synthesis and deposition of C3 by microglia/macrophages is associated with focal photoreceptor degeneration. Invest Ophthalmol Vis Sci 52:5347–5358

    Article  CAS  PubMed  Google Scholar 

  • Rutar M, Natoli R, Albarracin R et al (2012) 670-nm light treatment reduces complement propagation following retinal degeneration. J Neuroinflammation 9:257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schütt F, Davies S, Kopitz J et al (2000) Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci 41:2303–2308

    PubMed  Google Scholar 

  • Schutt F, Bergmann M, Holz FG et al (2003) Proteins modified by malondialdehyde, 4-hydroxynonenal, or advanced glycation end products in lipofuscin of human retinal pigment epithelium. Invest Ophthalmol Vis Sci 44:3663–3668

    Article  PubMed  Google Scholar 

  • Seo S, Krebs MP, Mao H et al (2012) Pathological consequences of long-term mitochondrial oxidative stress in the mouse retinal pigment epithelium. Exp Eye Res 101:60–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sohn JH, Kaplan HJ, Suk HJ et al (2000) Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Invest Ophthalmol Vis Sci 41:3492–3502

    CAS  PubMed  PubMed Central  Google Scholar 

  • Song D, Song Y, Hadziahmetovic M et al (2012) Systemic administration of the iron chelator deferiprone protects against light-induced photoreceptor degeneration in the mouse retina. Free Radic Biol Med 53:64–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang AL, Lukas TJ, Yuan M et al (2009) Changes in retinal pigment epithelium related to cigarette smoke: possible relevance to smoking as a risk factor for age-related macular degeneration. PLoS One 4:e5304

    Article  PubMed  PubMed Central  Google Scholar 

  • Weismann D, Hartvigsen K, Lauer N et al (2011) Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478:76–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams JAE, Greenwood J, Moss SE (2013) Retinal changes precede visual dysfunction in the complement factor H knockout mouse. PLoS One 8:e68616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodell A, Coughlin B, Kunchithapautham K et al (2013) Alternative complement pathway deficiency ameliorates chronic smoke-induced functional and morphological ocular injury. PLoS One 8:e67894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Z, Chen Y, Wang J et al (2011) Age-related retinopathy in NRF2-deficient mice. PLoS One 6:e19456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany

    Luciana M. Pujol-Lereis & Laura B. Kuhn

  2. Department of Ophthalmology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany

    Nicole Schäfer & Diana Pauly

  3. Department of Ophthalmology, Ralph H. Johnson VA Medical Center, Medical University of South Carolina and Research Service, 29401, Charleston, SC, USA

    Bärbel Rohrer

Authors
  1. Luciana M. Pujol-Lereis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicole Schäfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura B. Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bärbel Rohrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diana Pauly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Diana Pauly .

Editor information

Editors and Affiliations

  1. Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA

    Catherine Bowes Rickman

  2. Beckman Vision Center, University of California, San Francisco School of Medicine, San Francisco, California, USA

    Matthew M. LaVail

  3. Dean A. McGee Eye Inst., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA

    Robert E. Anderson

  4. University Hospital Zurich, Zurich, Switzerland

    Christian Grimm

  5. Case Western Reserve University Cleveland Clinic Lerner College of Med, Cleveland, Ohio, USA

    Joe Hollyfield

  6. Univ of Florida Dept of Ophthalmology/Arb R112, Gainesville, Florida, USA

    John Ash

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this paper

Cite this paper

Pujol-Lereis, L., Schäfer, N., Kuhn, L., Rohrer, B., Pauly, D. (2016). Interrelation Between Oxidative Stress and Complement Activation in Models of Age-Related Macular Degeneration. In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_13

Download citation

Publish with us

Policies and ethics

Search

Navigation