June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Recruited macrophages phagocytose damaged RPE mediating onset of angiogenesis
Author Affiliations & Notes
  • Jian Liu
    Ophthalmology, School of Clinical Sci, University of Bristol, Bristol, United Kingdom
  • David Copland
    Ophthalmology, School of Clinical Sci, University of Bristol, Bristol, United Kingdom
  • Shintaro Horie
    Ophthalmology, School of Clinical Sci, University of Bristol, Bristol, United Kingdom
  • Wei-Kang Wu
    Ophthalmology, School of Clinical Sci, University of Bristol, Bristol, United Kingdom
  • Mei Chen
    Centre for Vision and Vascular Science, Queen's University of Belfast, Belfast, United Kingdom
  • Yunhe Xu
    Ophthalmology, School of Clinical Sci, University of Bristol, Bristol, United Kingdom
  • Heping Xu
    Centre for Vision and Vascular Science, Queen's University of Belfast, Belfast, United Kingdom
  • Lindsay Nicholson
    Ophthalmology, School of Clinical Sci, University of Bristol, Bristol, United Kingdom
  • Andrew Dick
    Ophthalmology, School of Clinical Sci, University of Bristol, Bristol, United Kingdom
  • Footnotes
    Commercial Relationships Jian Liu, None; David Copland, None; Shintaro Horie, None; Wei-Kang Wu, None; Mei Chen, None; Yunhe Xu, None; Heping Xu, None; Lindsay Nicholson, None; Andrew Dick, Novartis (C), Novartis (F), GSK (F), Abbott (F)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 154. doi:https://doi.org/
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      Jian Liu, David Copland, Shintaro Horie, Wei-Kang Wu, Mei Chen, Yunhe Xu, Heping Xu, Lindsay Nicholson, Andrew Dick; Recruited macrophages phagocytose damaged RPE mediating onset of angiogenesis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):154. doi: https://doi.org/.

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

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Abstract

Purpose: Whilst data recognises a role for macrophage accumulation during chorioretinal neovascularisation (CNV) related to AMD, the exact mechanisms remain poorly defined and in particular the early events that drive angiogenesis. This study was to identify the contribution of retinal pigment epithelium (RPE) damage that conditions macrophage function and whether as such macrophage-mediated and VEGF-dependent angiogenesis occurs.

Methods: CNV was induced in wild-type C57BL/6J or CX3CR1(gfp/+) mice by laser. Macrophage accumulation was examined by confocal microscopy and flow cytometry. Expression of macrophage activation-related mediators was assessed by qPCR. VEGF expression was determined by immunostaining. CNV was assessed by isolectin B4 staining. An in vitro phagocytosis assay was applied to elucidate the role of RPE cell death in modulating macrophage phenotype.

Results: Laser induced focal disruption of RPE and Bruch’s membrane, cell death and DNA damage. Both retinal microglia and circulating myeloid cells were rapidly recruited to the site of injury 1-2 days post-laser, and displayed increased VEGF immuno-reactivity, importantly prior to any further exaggerated immune activation as evident by massive deposition of membrane attack complex. Following acute events in the laser model, macrophage infiltration and complement activation both recede 7-14 days post-laser when the angiogenesis has established. The novelty of the early events, occurring prior to endothelial proliferation, angiogenesis formation or complement deposition include: transient Arg-1+VEGF+ macrophage infiltration and such early recruited macrophages displayed high phagocytic and endocytic activity, engulfing fragments of damaged RPE at laser sites. In vitro data demonstrates that the Arg-1+VEGF+ macrophages are induced specifically by the uptake of damaged RPE.

Conclusions: The results demonstrate that early myeloid cell recruitment, by either microglia or monocytes, initiates the local proangiogenic response before complement activation or endothelial proliferation, which leads to the development of CNV. Furthermore, macrophages acquire an Arg-1+VEGF+ phenotype that drives early angiogenic events, which results from phagocytosis of damaged RPE. The data supports current therapeutic attempts aimed at preventing apoptotic or necrotic RPE cell death, as this may suppress the early trigger that drives the proangiogenic macrophage phenotype.

Keywords: 595 microglia • 701 retinal pigment epithelium • 453 choroid: neovascularization  
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