June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Neuroinflammatory Response to Retinal Ischemia/Reperfusion Injury in the Visual Axis and Complement Mediated Protection
Author Affiliations & Notes
  • Sean Silverman
    Cell Biology and Immunology, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
  • Gareth R Howell
    The Jackson Laboratory, Bar Harbor, ME
  • Simon W John
    The Jackson Laboratory, Bar Harbor, ME
    Howard Hughes Medical Institute, Bar Harbor, ME
  • Robert J Wordinger
    Cell Biology and Immunology, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
  • Abbot F Clark
    Cell Biology and Immunology, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
  • Footnotes
    Commercial Relationships Sean Silverman, None; Gareth Howell, None; Simon John, None; Robert Wordinger, None; Abbot Clark, Genzyme-Sanofi (C), ISIS Pharmaceuticals (C), Reata Pharmaceuticals (F), Sanofi-Fovea (C)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2417. doi:
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      Sean Silverman, Gareth R Howell, Simon W John, Robert J Wordinger, Abbot F Clark; Neuroinflammatory Response to Retinal Ischemia/Reperfusion Injury in the Visual Axis and Complement Mediated Protection. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2417.

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

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Abstract

Purpose: Studies show C1q is essential during synaptic refinement in removal of weaker RGC axons in the brain. C1qa was identified as an early stage differentially expressed gene in the ONH and retina prior to glaucomatous damage, and DBA/2J mice lacking C1qa displayed a delay in the onset of an injury phenotype. We tested the hypothesis that deficiencies in C1qa will mediate neuroprotection in mice receiving RI/R.

Methods: Left eyes of WT and C1qa+/- mice (n=7-8) were cannulated in their anterior chamber, and IOP was raised to 120mmHg for 60 minutes. Right eyes served as controls. ERGs were performed 7, 14, 21, and 28 days after injury. Tissues were harvested using the same time points. Eyes and brains were fixed in 4% PFA and either paraffin embedded for H&E staining or frozen for immunofluorescence. All quantifications were performed in ImageJ (NIH) and statistics calculated using SigmaPlot (Systat).

Results: WT mice displayed changes in C1q expression in the superior colliculus (SC) by day 7 in the contralateral (ischemic) compared to the ipsilateral (control) hemisphere. Correspondingly, microglial density was significantly increased in the contralateral (2.55 ± 0.295%, p=0.006) compared to the ipsilateral (1.27 ± 0.228%) hemisphere on day 7. No significant differences in astrocyte density between hemispheres were observed. From day 7 to 28 there was a significant increase in microglial population in the ipsilateral hemisphere (p<0.001). Similarly, there was a significant increase in astrocyte density from day 7 to 28 in the ipsilateral (p=0.009) and contralateral (p=0.02) SC. When retinal thickness was compared between WT and C1qa+/- ischemic eyes, whole retina (p=0.01) and INL (p<0.001) thicknesses were significantly different. Ischemic injury had no significant effect on retinal thickness in C1qa+/- mice. No differences were observed in ERG b-wave amplitudes between C1qa genotypes.

Conclusions: Our studies suggest injury in the eye facilitates a neuroinflammatory response in the SC. RI/R causes early changes in C1q expression in the contralateral SC. However, significant increases in glial cell density and activation occur in hemispheres corresponding to ischemic and uninjured eyes. C1qa-deficiency protects the inner retina, but has no effect upon improving visual function. We predict future studies with C1qa-/- mice will mediate greater protection against RI/R injury.

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