June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Endocannabinoids reduce NF-κB signaling in Müller glia and promote the formation of Müller glia-derived progenitor cells in damaged retinas
Author Affiliations & Notes
  • Warren A Campbell IV
    Neuroscience, The Ohio State University, Columbus, Ohio, United States
  • Sydney Blum
    Neuroscience, The Ohio State University, Columbus, Ohio, United States
  • Alana Reske
    Neuroscience, The Ohio State University, Columbus, Ohio, United States
  • Andrew Fischer
    Neuroscience, The Ohio State University, Columbus, Ohio, United States
  • Footnotes
    Commercial Relationships   Warren Campbell IV, None; Sydney Blum, None; Alana Reske, None; Andrew Fischer, None
  • Footnotes
    Support  EY022030-08 , EY027267-04
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1662. doi:
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      Warren A Campbell IV, Sydney Blum, Alana Reske, Andrew Fischer; Endocannabinoids reduce NF-κB signaling in Müller glia and promote the formation of Müller glia-derived progenitor cells in damaged retinas. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1662.

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

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Abstract

Purpose : Endocannabinoids (eCB) are lipid-based neurotransmitters that are known to influence visual function and perception. Additionally, eCBs are known to reduce inflammatory signaling in pathological states. However, little is known about the role of the eCB system in modulating inflammation after damage and during reprogramming Müller glia (MG) into progenitor cells (MGPCs).

Methods : Chick retinas after excitotoxic damage were implemented as a model of partial retinal regeneration. The expression of eCB signaling genes were analyzed using single cell RNA sequencing (10X Genomics) in postnatal chicks (P7-P21) with intravitreal injection of NMDA (2µmol/dose). Small molecule drugs targeted the CNR1 receptor and eCB synthesis and degradation. MGPCs were identified via 5-ethynyl-2'-deoxyuridine incorporation. Microglia morphology was characterized via Sholl Analysis (ImageJ). Retinal NF-κB activation was determined using cis-NF-κBEGFP reporter mice. Statistical Significance was assessed via a Student’s T test, Wilcox Rank Sum test with Bonferroni correction, one-way ANOVA, and Tukey’s test.

Results : MG express eCB signaling and synthesis genes (CNR1, PLCB, NAPELPD, DAGLB, MGLL). Intravitreal injections of eCB increased numbers of MGPCs after damage (n = 8, p < 0.05). The CNR1 agonist win55, 212-2 (n = 8, p < 0.05) and inhibition of eCB-degradation with JJKK048 (n = 8, p < 0.05) resulted in comparable increases in numbers of MGPCs. The CNR1 antagonist rimonabant (n = 8, p < 0.05) and lipase inhibitor Orlistat (n = 8, p < 0.05) reduced MGPC formation. However, chick microglia reactivity (proliferation, accumulation, area, CD45 intensity, morphology) after damage was unaffected by all treatment conditions (n = 8, p > 0.05). In damaged mouse retinas, numbers of NF-κB-GFP+ MG increased after rimonabant treatment (n = 4, p < 0.05) and decreased with win55, 212-2 (n = 4, p < 0.05) and eCBs (n = 4, p < 0.05).

Conclusions : MG respond to inflammatory signaling factors, which influence the capacity of MG to transition into a proliferative state. eCBs result in fewer MG with NF-κB activation in mouse, and promote MGPC formation in the chick, without significant changes to microglia reactivity. These findings suggest that eCB inhibits NF-κB signaling in MG which promotes MPGC formation.

This is a 2021 ARVO Annual Meeting abstract.

 

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