June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
TLR4 plays an important role in regulating ZO-1 and occludin levels, as well as retinal damage following ischemia-reperfusion injury
Author Affiliations & Notes
  • Li Liu
    Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States
  • Youde Jiang
    Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States
  • Elizabeth Curtiss
    Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States
  • Jena J Steinle
    Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States
    Ophthalmology, Wayne State University, Detroit, Michigan, United States
  • Footnotes
    Commercial Relationships   Li Liu, None; Youde Jiang, None; Elizabeth Curtiss, None; Jena Steinle, None
  • Footnotes
    Support  R01EY022330
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5203. doi:
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      Li Liu, Youde Jiang, Elizabeth Curtiss, Jena J Steinle; TLR4 plays an important role in regulating ZO-1 and occludin levels, as well as retinal damage following ischemia-reperfusion injury
      . Invest. Ophthalmol. Vis. Sci. 2017;58(8):5203.

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

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Abstract

Purpose : Recent work has suggested that diabetic retinopathy has a strong inflammatory component. Our group reported that a novel b-adrenergic receptor agonist, Compound 49b, reduced toll-like receptor 4 (TLR4) signaling in the diabetic retina and in retinal endothelial cells. In this study, we wanted to investigate whether TLR4 levels regulate endothelial cell permeability, including zonula occluden 1 (ZO-1) and occludin levels, as well as, if TLR4 plays an important role in ischemia-reperfusion (I/R)-induced retinal vascular damage and neuronal loss.

Methods : TLR4 floxed mice (B6 Cg-Tlr4tm1.1karp/J) and B6.FVB-Tg (cdh5-cre)7Mlia/J Cre mice purchased from Jackson lab were cross bred to produce endothelial cell specific TLR4 conditional knockout mice. TLR4 overexpressing mice were acquired from Dr. Fukuchi. TLR4 knockout and overexpression mice were selected by genotyping and kept for 3 months prior the experiments. Some mice from each group were used for Western blotting for TLR4, ZO-1, and occludin. Additionally, additional knockout and overexpressing mice were subjected to ischemia-reperfusion (I/R) followed by neuronal analyses at 2 days and vascular analyses at 10 days. Mice in all groups were assessed for changes in permeability using fluorescein angiography.

Results : Protein levels of ZO-1 and occludin were decreased in the TLR4 floxed mice compared to TLR4 Cre-Lox. TLR4 overexpressing mice had much lower ZO-1 and occludin levels than their control littermates. Ten days after I/R, TLR4 overexpressing mice had significantly more degenerate capillaries than their littermates. TLR4 Cre-Lox had fewer degenerate capillaries than floxed mates. At 24 hour after I/R, TLR4 overexpressing and TLR4 floxed mice had increased leakage when compared to the control littermates and TLR4 Cre-Lox, respectively.

Conclusions : The data demonstrate that TLR4 plays an important role in regulation of the tight junction permeability, as well as vascular and neuronal damage in the retina. TLR4 overexpression enhanced leakage following I/R, which was associated with more degenerate capillaries and neuronal loss. Taken together, the data suggest that inhibition of TLR4 may be protective to the damaged retina.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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