An allosteric interleukin-1 receptor modulator mitigates inflammation and photoreceptor toxicity in a model of retinal d
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(2020) 17:359
RESEARCH
Open Access
An allosteric interleukin-1 receptor modulator mitigates inflammation and photoreceptor toxicity in a model of retinal degeneration Rabah Dabouz1,2,3, Colin W. H. Cheng1,2,3, Pénélope Abram2, Samy Omri2, Gael Cagnone3, Khushnouma Virah Sawmy3, Jean-Sébastien Joyal3, Michel Desjarlais2, David Olson4, Alexander G. Weil5, William Lubell6, José Carlos Rivera2,3 and Sylvain Chemtob1,2,3*
Abstract Background: Inflammation and particularly interleukin-1β (IL-1β), a pro-inflammatory cytokine highly secreted by activated immune cells during early AMD pathological events, contribute significantly to retinal neurodegeneration. Here, we identify specific cell types that generate IL-1β and harbor the IL-1 receptor (IL-1R) and pharmacologically validate IL-1β’s contribution to neuro-retinal degeneration using the IL-1R allosteric modulator composed of the amino acid sequence rytvela (as well as the orthosteric antagonist, Kineret) in a model of blue light–induced retinal degeneration. Methods: Mice were exposed to blue light for 6 h and sacrificed 3 days later. Mice were intraperitoneally injected with rytvela, Kineret, or vehicle twice daily for 3 days. The inflammatory markers F4/80, NLRP3, caspase-1, and IL-1β were assessed in the retinas. Single-cell RNA sequencing was used to determine the cell-specific expression patterns of retinal Il1b and Il1r1. Macrophage-induced photoreceptor death was assessed ex vivo using retinal explants co-cultured with LPS-activated bone marrow–derived macrophages. Photoreceptor cell death was evaluated by the TUNEL assay. Retinal function was assessed by flash electroretinography. (Continued on next page)
* Correspondence: [email protected] 1 Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada 2 Departments of Pediatrics, Ophthalmology, and Pharmacology, Hôpital Maisonneuve-Rosemont Research Center, 5415 Boul L’Assomption, Montreal, QC H1T 2 M4, Canada Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made availa
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