April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
ProNGF Stimulates Retinal Inflammation Via Activation of p75NTR
Author Affiliations & Notes
  • Azza B. El-Remessy
    Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia
  • Mohammed M. Al-Gayyar
    Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia
  • Mohammed A. Abdelsaid
    Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia
  • Suraporn Matragoon
    Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia
  • Bindu A. Pillai
    Clinical and Experimental Therapeutics, University of Georgia, Augusta, Georgia
  • H Uri Saragovi
    Pharmacology, McGill University, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships  Azza B. El-Remessy, None; Mohammed M. Al-Gayyar, None; Mohammed A. Abdelsaid, None; Suraporn Matragoon, None; Bindu A. Pillai, None; H Uri Saragovi, None
  • Footnotes
    Support  SDG-AHA, CDA-JDRF to ABE and CIHR to US
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 1001. doi:https://doi.org/
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      Azza B. El-Remessy, Mohammed M. Al-Gayyar, Mohammed A. Abdelsaid, Suraporn Matragoon, Bindu A. Pillai, H Uri Saragovi; ProNGF Stimulates Retinal Inflammation Via Activation of p75NTR. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1001. doi: https://doi.org/.

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

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Abstract

Purpose: : We have previously shown significant accumulation of the pro-form of nerve growth factor (proNGF) and its receptor p75NTR in diabetic rat retinas and Muller cells. The purpose of this study is to elucidate the role of proNGF/p75NTR axis in sustaining glial activation, and expression of inflammatory mediators in vitro and in vivo.

Methods: : Overexpression of proNGF in SD rats was achieved by intravitreal injection of the GFP-proNGF plasmid (20 µg) expressing the protease cleavage resistant proNGF construct. Expression of p75NTR was silenced using co-intravitreal injection of siRNA for 1-week or shRNA for 4-weeks. Expression of proNGF, TNF-alpha, IL-1-beta and NFkB were quantified by immunohistochemistry and Western-Blot. As an ex vivo correlate, Muller rMC-1 cells were cultured in high glucose and stimulated with proNGF in the presence or absence of p75NTR inhibitor.

Results: : Overexpression of proNGF in rat retina induced expression of p75NTR, activated glial Muller cells as indicated by GFAP staining, and upregulated the pro-inflammatory transcription factor NFkB. After 1-week, proNGF induced expression of TNF-alpha and IL-1-beta, and this was blocked by p75NTR siRNA. After 4-weeks, proNGF sustained the expression of itself, TNF-alpha and IL-1-beta, and this was blocked by p75NTR shRNA. In high glucose maintained rMC-1 cultures, proNGF induced expression of p75NTR, release of its ICD, and upregulation of of NFkB, which resulted in sustained expression proNGF as well as TNF-alpha. These effects were blunted by the selective p75NTR antagonist.

Conclusions: : Similar to diabetes, overexpression of proNGF in normal rat retina induced up-regulation of p75NTR and NFkB expression leading to inflammatory cascades. These effects were associated with induction and sustaining expression of proNGF, TNF-alpha and IL-1B that were blocked by inhibiting p75NTR expression. Thus, inhibiting p75NTR may be an effective strategy in diabetic retinopathy.

Keywords: diabetic retinopathy • inflammation • Muller cells 
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