June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Caspase-1 activation and IL-1 secretion are counteracted by elovanoids in retinal cells, engaging NOD2 signaling pathway activation
Author Affiliations & Notes
  • Marie-Audrey Ines Kautzmann
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Aram Asatrian
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Nicolas G Bazan
    Neuroscience Center of Excellence, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Footnotes
    Commercial Relationships   Marie-Audrey Kautzmann None; Aram Asatrian None; Nicolas Bazan None
  • Footnotes
    Support  NEI grant R01EY005121 (NGB) and the EENT Foundation (NGB)
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4469. doi:
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      Marie-Audrey Ines Kautzmann, Aram Asatrian, Nicolas G Bazan; Caspase-1 activation and IL-1 secretion are counteracted by elovanoids in retinal cells, engaging NOD2 signaling pathway activation. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4469.

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

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Abstract

Purpose : Nucleotide binding oligomerization domain 2 (NOD2) is an intracellular sensor of bacterial peptidoglycan and belong to the Nod-like receptor (NLR) family of innate immune proteins that play pleiotropic roles in inflammatory responses. Docosahexaenoic acid (DHA)-derived lipid mediators, elovanoids (ELVs), are downregulated in the retinas and retinal pigment epithelium (RPE) of mutant Adipor1 and Mfrp mice, leading to a selective reduction of ELV and NPD1 precursors. This leads to impaired retinal function and loss of photoreceptor cells. Now we aim to determine whether ELVs reduce chronic inflammation by modulating NOD2 activation in the NLRP3 inflammasome response.

Methods : In vitro analysis on RPE cells were pre-treated for 30 min with 300 nM ELV. Cellular stress was induced using IL-1α (24 h) followed by H2O2 (1200 μM for 6-8 h) or oxidized LDL (ox-LDL, 120-150 µg/ml) for 24 h. In vivo analyses were conducted with eyes from Adipor1-/- and Mfrprd6 mice. Detection of NOD2 and NRLP3 inflammasome markers was done using qPCR, Western Blot, and immunocytochemistry/histochemistry.

Results : We showed that IL-1α or ox-LDL increased the expression of NLRP3 pro-inflammatory signaling markers in RPE cells. ELVs suppress expression of IL-1β, IL-6, IL-8, and NOD2 by 80%, 90%, 65%, and 60%, respectively (IL-1α activation), and 80% and 65% (ox-LDL) for IL-8 and NOD2, respectively. Adipor1-/- and Mfrprd6 had a 47% and 189% increase in caspase 1 activity, respectively, reported by FAM-FLICA assay.

Conclusions : ELVs downregulate the expression of innate immunity markers, e.g., NOD2 activation signaling cascade: IL-1β, IL-6, as well as NLRP3 inflammasome and its activation response genes (IL-23α and IL-1β). Adipor1-/- and Mfrprd6 are susceptible to uncontrolled inflammatory events leading to microglial/macrophage invasion and caspase 1-dependent tissue damage, suggesting pyroptosis action. Thus, ELVs open potential therapeutics avenues targeting NLR family proteins.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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