September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Investigating a role for Toll like receptor signaling in the pathogenesis of Age Related Macular Degeneration (AMD).
Author Affiliations & Notes
  • Kelly Mulfaul
    Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland
  • Ema Ozaki
    Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland
  • Kiva Brennan
    Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland
    The National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland
  • Matthew Campbell
    Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
  • Sarah Doyle
    Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland
    The National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland
  • Footnotes
    Commercial Relationships   Kelly Mulfaul, None; Ema Ozaki , None; Kiva Brennan, None; Matthew Campbell , None; Sarah Doyle, None
  • Footnotes
    Support  Health Research Board and The Brightfocus Foundation
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5010. doi:
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    • Get Citation

      Kelly Mulfaul, Ema Ozaki, Kiva Brennan, Matthew Campbell, Sarah Doyle; Investigating a role for Toll like receptor signaling in the pathogenesis of Age Related Macular Degeneration (AMD).. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5010.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : One of the biological signatures observed in AMD is the marked deposition sub-retinal pigment epithelium (RPE) of complement factor 3 (C3). Neither the reason nor the outcome of C3 deposition is fully understood. We hypothesize that sterile danger associated molecular patterns (DAMPs) found in the degenerating retina activate Toll like receptor (TLR) signaling pathways to induce C3 expression.

Methods : Murine bone marrow derived macrophages, human monocytes and human RPE cells were treated with various TLR ligands over time and assayed by qPCR and Western Blot for C3 expression and secretion.

Results : C3 expression is significantly upregulated in response to TLR2, 3, 4, 7, 8 and 9 ligation in macrophages and TLR2, 3 and 4 ligation in the RPE. C3 is increased at the level of gene expression in response to TLR activation. Furthermore TLR activation results in an increase of C3 secretion from RPE cells and human monocytes. Expression of C3 is regulated by TIR adapter proteins Mal/TIRAP, MyD88 and TRIF.

Conclusions : Despite the complement cascade and TLRs both being critical components of the innate immune response little is known about the interaction between these two pathways. We have demonstrated that TLR activation can promote the expression and secretion of C3, the key complement factor in all three complement cascades. Given the array of possible TLR ligands available in the environment of the degenerating RPE/retina, it is possible that the sheer volume of secretion in response to TLR activation promotes C3 deposition potentially compromising the integrity of the RPE outer blood-retina barrier (oBRB).

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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