June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
NLRP3 inflammasome activation affects neuroretinal function in diabetic retinopathy
Author Affiliations & Notes
  • Xiaoyu Cai
    University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Bradley Gelfand
    Center for Advanced Vision Science University of Virginia, Charlottesville, Virginia, United States
    University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Jayakrishna Ambati
    Center for Advanced Vision Science University of Virginia, Charlottesville, Virginia, United States
    University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Footnotes
    Commercial Relationships   Xiaoyu Cai None; Bradley Gelfand None; Jayakrishna Ambati None
  • Footnotes
    Support  R01EY031039
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 948 – A0417. doi:
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    • Get Citation

      Xiaoyu Cai, Bradley Gelfand, Jayakrishna Ambati; NLRP3 inflammasome activation affects neuroretinal function in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2022;63(7):948 – A0417.

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

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Abstract

Purpose : Evidence suggests that inflammasome activity contributes to the pathogenesis of diabetic retinopathy (DR), but there remains uncertainty in the role of the NLRP3 inflammasome in DR. We sought to elucidate the timing of inflammasome activation and evaluate the involvement of NLRP3 inflammasome constituents including NLRP3, the adaptor ASC, and the protease Caspase-1 using a streptozotocin (STZ) induced DR mouse model.

Methods : The STZ model was used to induce diabetes (DM) in C57BL/6J wild type (WT) mice (male (m) N=60; female (f) N=20) as well as Caspase-1 knock out (KO) (m N=7; f N=5), ASC KO (m N=9; f N=9), and NLRP3 KO (m N=9; f N=8) mice. Vehicle control was used for control (CTL) mice of each genotype and sex. After one, three, and eight months of hyperglycemia, bilateral eyes were harvested with one eye being embedded for cryo-sectioning and the other being dissected for whole retina collection. Collected neuroretina were evaluated for inflammasome activity with immunoblotting. Gliosis and neuroinflammation were visualized through immunofluorescence staining of cryosectioned eyes for NLRP3 inflammasome constituents. Retinal neurodegeneration was also evaluated using scotopic electroretinography (ERG).

Results : At one and three months after STZ induction, immunoblotting of whole retinal lysates showed minimal increase of inflammasome activation in WT DM mice compared to WT CTL mice. On ERG evaluation at three months, there was a 23.1% decrease in a-wave and a 32.3% decrease in b-wave between DM and CTL WT mice. For Caspase-1 KO mice, there was a lesser decrease of 10.8% and 21.8% in a- and b-waves respectively, and in ASC KO mice there was also a lessened decrease of 5% in a-wave and 18.3% in b-wave between DM and CTL mice.

Conclusions : Our results suggest that while inflammasome activation may not be evident on protein analysis, on ERG evaluation there is a decrease in readings that may be indicative of a reduction in neuroretinal function by three months of DR. Additionally, the reduced loss of electrical function in both Caspase-1 KO and ASC KO mice may represent a partial rescue of neuroretinal function when components of the NLRP3 inflammasome are absent. This finding helps to establish a direct connection between inflammasome constituents to the pathological processes of DR. Further investigation is needed to elucidate the precise role of NLRP3 inflammasome activation in the pathogenesis of DR.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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