June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Sphingosine 1 Phosphate Signaling Enhances NF-κB Activation and Suppresses Muller Glia Reprogramming in the Injured Retina
Author Affiliations & Notes
  • Olivia Taylor
    Neuroscience, The Ohio State University, Columbus, Ohio, United States
  • Andy J Fischer
    Neuroscience, The Ohio State University, Columbus, Ohio, United States
  • Footnotes
    Commercial Relationships   Olivia Taylor None; Andy Fischer None
  • Footnotes
    Support  NIH Grant R01 EY022030-09
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1868. doi:
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      Olivia Taylor, Andy J Fischer; Sphingosine 1 Phosphate Signaling Enhances NF-κB Activation and Suppresses Muller Glia Reprogramming in the Injured Retina. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1868.

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

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Abstract

Purpose : Harnessing the regenerative potential of Muller glia (MG) may lead to the development of novel therapies reversing neuronal cell loss in sight-threatening diseases. In this study, we identify sphingosine 1 phosphate (S1P) as a critical activator of NF-κB, an inflammatory signaling pathway shown to suppress both the proliferation of Muller glia-derived progenitor cells (MGPCs) in chick retinas and the reprogramming of Ascl1-overexpressing MG in mouse retinas. We hypothesize that inhibiting S1P signaling may promote the formation of MGPCs in injured retinas.

Methods : NF-κB-eGFP transgenic mice (n=6, P77-144) received intravitreal injections of 2 µg/dose PF543, a sphingosine kinase 1 inhibitor, with 14.72 µg NMDA (an excitotoxin); the contralateral eye received NMDA + vehicle. Eyes were enucleated, fixed, and sectioned. Retinas were immunolabeled for GFP and Sox2. Co-labeled cells were quantified, and statistical analyses were conducted using a two-tailed paired t-test. A similar paradigm was conducted with SEW2871 (S1PR1 agonist) (2 ug/dose, n=7, P91-96).
Young postnatal chicks (n=6, P7) received intraocular injections of 5 µg/dose PF543 with 73 µg NMDA and 2 µg EdU. Fixed retinal sections were immunolabeled for EdU and Sox2, and co-labeled cells were quantified and analyzed with a two-tailed paired t-test. A similar paradigm was conducted with SEW2871 (5 ug/dose, n=6, P7).

Results : NMDA-damaged mouse retinas treated with PF543 had significantly fewer NF-κB+ MG (5.17±2.14) than control retinas (10.17±4.26, p=0.0035). Mouse retinas treated with SEW2871, without damage, had significantly more NF-κB+ MG (8.21±4.68) than control retinas (2.00±1.85, p=0.0091). Chick retinas treated with PF543 and NMDA showed greater proliferation of MGPCs (78.67±8.09) than control damaged retinas (44.5±13.61, p<0.0001). A decrease in proliferation was observed in injured chick retinas treated with SEW2871 (56.5±8.04) compared to control retinas (69.17±17.38, p=0.0296).

Conclusions : These results suggest that S1P signaling may suppress MGPC formation in part through NF-κB. We previously found that S1PR1 inhibition was not sufficient to decrease NF-κB or enhance MGPC formation; other S1P receptors may be compensatory in the absence of S1PR1 signaling. In this study, we found that S1P synthesis and receptor activation may be a critical inhibitor of MG reprogramming in chick and mouse retinas.

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

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