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Here, we identify specific cell types that generate IL-1\u03b2 and harbor the IL-1 receptor (IL-1R) and pharmacologically validate IL-1\u03b2\u2019s 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\u2013induced retinal degeneration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Mice were exposed to blue light for 6\u2009h and sacrificed 3\u2009days later. Mice were intraperitoneally injected with rytvela, Kineret, or vehicle twice daily for 3\u2009days. The inflammatory markers F4\/80, NLRP3, caspase-1, and IL-1\u03b2 were assessed in the retinas. Single-cell RNA sequencing was used to determine the cell-specific expression patterns of retinal <jats:italic>Il1b<\/jats:italic> and <jats:italic>Il1r1.<\/jats:italic> Macrophage-induced photoreceptor death was assessed ex vivo using retinal explants co-cultured with LPS-activated bone marrow\u2013derived macrophages. Photoreceptor cell death was evaluated by the TUNEL assay. Retinal function was assessed by flash electroretinography.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Blue light markedly increased the mononuclear phagocyte recruitment and levels of inflammatory markers associated with photoreceptor death. Co-localization of NLRP3, caspase-1, and IL-1\u03b2 with F4\/80<jats:sup>+<\/jats:sup> mononuclear phagocytes was clearly detected in the subretinal space, suggesting that these inflammatory cells are the main source of IL-1\u03b2. Single-cell RNA sequencing confirmed the immune-specific expression of <jats:italic>Il1b<\/jats:italic> and notably perivascular macrophages\u00a0in light-challenged mice, while <jats:italic>Il1r1<\/jats:italic> expression was found primarily in astrocytes, bipolar, and vascular cells. Retinal explants co-cultured with LPS\/ATP-activated bone marrow\u2013derived macrophages displayed a high number of TUNEL-positive photoreceptors, which was abrogated by rytvela treatment. IL-1R antagonism significantly mitigated the inflammatory response triggered in vivo by blue light exposure, and rytvela was superior to Kineret in preserving photoreceptor density and retinal function.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>These findings substantiate the importance of IL-1\u03b2 in neuro-retinal degeneration and revealed specific sources of <jats:italic>Il1b<\/jats:italic> from perivascular MPs, with its receptor <jats:italic>Ilr1<\/jats:italic> being separately expressed on surrounding neuro-vascular and astroglial cells. They also validate the efficacy of rytvela-induced IL-1R modulation in suppressing detrimental inflammatory responses and preserving photoreceptor density and function in these conditions, reinforcing the rationale for clinical translation.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-020-02032-8","type":"journal-article","created":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T07:08:33Z","timestamp":1606460913000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["An allosteric interleukin-1 receptor modulator mitigates inflammation and photoreceptor toxicity in a model of retinal degeneration"],"prefix":"10.1186","volume":"17","author":[{"given":"Rabah","family":"Dabouz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin W. 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