September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Amelioration of Amyloid β induced retinal inflammatory responses by a LXR agonist TO901317 is associated with inactivation of the NF-κB signaling and NLRP3 Inflammasome
Author Affiliations & Notes
  • Bo Lei
    Ophthalmology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
    Chongqing Key Laboratory of Ophthalmology, Chongqing, Chongqing, China
  • Chunyan Lei
    Ophthalmology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
    Chongqing Key Laboratory of Ophthalmology, Chongqing, Chongqing, China
  • Footnotes
    Commercial Relationships   Bo Lei, None; Chunyan Lei, None
  • Footnotes
    Support  National Natural Science Foundation of China grants (81271033, 81470621), Chongqing Science and Technology Commission (2014pt-sy10002) and National Key Clinical Specialties Construction Program of China.
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Bo Lei, Chunyan Lei; Amelioration of Amyloid β induced retinal inflammatory responses by a LXR agonist TO901317 is associated with inactivation of the NF-κB signaling and NLRP3 Inflammasome. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Amyloid β (Aβ) peptide, a major component of drusen which is the hallmark of age-related macular degeneration (AMD), is known to facilitate inflammatory responses in vivo. The purpose of this study was to investigate whether activation of liver X receptors (LXRs) ameliorates retinal inflammatory responses induced by Aβ1-40 and to explore the underlying mechanism.

Methods : Retinal inflammatory responses were induced with intravitreal injection of Aβ1-40 peptide in C57BL/6J mice. A synthetic LXR ligand TO901317 (TO90, 50 mg/kg/d) or vehicle was intragastrically administrated from 3 days before to 4 days after Aβ1-40 injection. The expressions of pro-inflammatory genes TNF-α and IL-6 were examined by real-time PCR. The levels of LXRα, LXRβ and their target gene ABCA1, as well as NLRP3, caspase-1 and IL-1β in the neuroretina and the RPE/choroid complex were detected with real-time PCR and western blotting. The changes of phosphorylation of IκBα (p-IκB-α) in the neuroretina and the RPE/choroid complex were detected with western blotting. Retinal function was assessed with electroretinography (ERG).

Results : The mRNA expressions of LXRα and LXRβ in the neuroretina of the Aβ1-40-injected mice decreased. No significant difference was found on the protein expressions of LXRs and ABCA1 in both neuroretina and RPE/choroid complex between the Aβ1-40-injected group and the untreated group. TO90 enhanced the expressions of LXRα and ABCA1 at both mRNA and protein levels in the Aβ1-40-injected mice, while the LXRβ expression was unchanged. TO90 preserved ERG a- and b-wave amplitudes in the Aβ1-40-treated mice. Meanwhile, compared with the Aβ1-40 plus vehicle-treated group, the mRNA levels of the pro-inflammatory cytokines TNF-α and IL-6 were significantly decreased in the Aβ1-40 plus TO90-treated group. Furthermore, TO90 downregulated the phosphorylation of IκBα as well as the expressions of NLRP3, caspase-1 and IL-1β in the neuroretina and the RPE/choroid complex in the Aβ1-40-injected animals.

Conclusions : Activation of LXRα and ABCA1 with TO90 inhibits retinal inflammatory responses induced by Aβ1-40 in mice. It appears that the anti-inflammatory effect is mediated mainly by LXRα. The beneficial effect is associated with inhibition of the NF-κB signaling pathway and the NLRP3/caspase-1/IL-1β axis.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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