September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The yin and yang of the complement cascade in glaucoma – the importance of timing and location
Author Affiliations & Notes
  • Gareth R Howell
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Pete Williams
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Jeffrey Harder
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • James Tribble
    Cardiff University, Cardiff, United Kingdom
  • Keating Pepper
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Stephen Cross
    Cardiff University, Cardiff, United Kingdom
  • Paul Morgan
    Cardiff University, Cardiff, United Kingdom
  • James Edwards Morgan
    Cardiff University, Cardiff, United Kingdom
  • Simon W John
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Footnotes
    Commercial Relationships   Gareth Howell, None; Pete Williams, None; Jeffrey Harder, None; James Tribble, None; Keating Pepper, None; Stephen Cross, None; Paul Morgan, None; James Morgan, None; Simon John, None
  • Footnotes
    Support  NIH NEI EY021525
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Gareth R Howell, Pete Williams, Jeffrey Harder, James Tribble, Keating Pepper, Stephen Cross, Paul Morgan, James Edwards Morgan, Simon W John; The yin and yang of the complement cascade in glaucoma – the importance of timing and location. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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

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  • Supplements
Abstract

Purpose : Activation of the complement cascade is a consistent feature of human and experimental glaucoma but the precise role of complement has not been elucidated. Previously, we have used DBA/2J mice, a widely used mouse model of glaucoma, to show that complement activation occurs very early in the retina and optic nerve head (ONH), prior to retinal ganglion cell (RGC) loss and optic nerve degeneration. Further, C1qa – encoding C1q the activating molecule of the classical pathway – is expressed by microglia/macrophages and RGCs and glaucomatous RGC loss is greatly reduced in DBA/2J mice deficient in C1q. Collectively, these data suggest that complement activation is important in the initiation of glaucomatous damage.

Methods : We have used a combination of transcriptional profiling, immunofluorescence and genetic and pharmacological inhibition using animal models and cell-based strategies to investigate the role of complement in glaucoma.

Results : We now show that deficiency of C1q in DBA/2J mice or pharmacological inhibition of C1 in a rat bead model of ocular hypertension is sufficient to preserve the dendritic and synaptic architecture of RGCs during the early stages of glaucoma. However, additional data suggests that complement activation can play both beneficial and damaging roles depending on timing and location. Interrogation of transcriptional profiling data suggests that C3 and other components of the complement alternative pathway are upregulated by astrocytes in the ONH, prior to upregulation of components of the classical pathway. In contrast to C1q, deficiency of C3 exacerbates glaucomatous neurodegeneration in DBA/2J. To clarify the role of astrocytic C3, we performed transcriptional profiling of C3-sufficient and C3-deficient astrocytes and identified the mitogen-activated protein kinase (MAPK) pathway as differentially up-regulated in C3-deficient astrocytes. Components of the MAPK pathway are expressed by ONH astrocytes and the pharmacological inhibition of epidermal growth factor receptor (EGFR) – an initiating molecule in the MAPK pathway – significantly increased RGC loss in DBA/2J mice.

Conclusions : Our results suggest that astrocytic C3 and EGFR act to mitigate the damaging effects of IOP elevation on the ONH. The augmentation of these early astrocytic responses could form the basis for the protection of RGC structure and function in early glaucoma.

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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