Research Paper Volume 13, Issue 18 pp 22040—22058
A2E-induced inflammation and angiogenesis in RPE cells in vitro are modulated by PPAR-α, -β/δ, -γ, and RXR antagonists and by norbixin
- 1 Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris F-75012, France
- 2 Biophytis, Sorbonne Université, Paris 75005, France
- 3 Fondation Ophtalmologique Rothschild, Paris F-75019, France
- 4 Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Received: November 21, 2020 Accepted: September 3, 2021 Published: September 20, 2021https://doi.org/10.18632/aging.203558
How to Cite
Copyright: © 2021 Fontaine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing angiogenesis and inflammation. A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-α. Here we show that A2E binds and transactivates also peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR). 9’-cis-norbixin, a di-apocarotenoid is also a ligand of these nuclear receptors (NR). Norbixin inhibits PPAR and RXR transactivation induced by A2E. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-κB and AP-1 transactivation and mRNA expression of the inflammatory interleukins (IL) -6 and -8 and of vascular endothelial growth factor (VEGF) enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression in response to A2E. Selective PPAR-α, -β/δ and –γ antagonists inhibit the expression of IL-6 and IL-8 while only the antagonist of PPAR-γ inhibits the transactivation of NF-κB following A2E exposure. In addition, a cocktail of all three PPARs antagonists and also HX531, an antagonist of RXR reproduce norbixin effects on inflammation. Altogether, A2E’s deleterious biological effects could be inhibited through PPAR and RXR regulation. Moreover, the modulation of these NR by norbixin may open new avenues for the treatment of AMD.
A2E: N-retinylidene-N-retinylethanolamine; A2-PE: phosphatidylethanolamine-bisretinoid; AKT: protein kinase B; AMD: age-related macular degeneration; AP-1: activator protein 1; ATRA: all-trans-retinoic acid; CCL2: C-C motif chemokine ligand 2; ERK: extracellular signal-regulated signal; IL: interleukin; LXRs: liver X receptor; NBX: norbixin; NR: nuclear receptors; MMP9: matrix metalloproteinase 9; PPAR: peroxisome proliferator activated receptors; RARs: retinoic acid receptors; RPE: retinal pigment epithelial cells; RXR: retinoic X receptor; VEGF: vascular endothelial growth factor.