title: IL-33 amplifies an innate immune response in the degenerating retina.
abstract: Age-related macular degeneration (AMD), a leading cause of vision impairment in the ageing population, is characterized by irreversible loss of retinal pigment epithelial (RPE) cells and photoreceptors and can be associated with choroidal neovascularization. Mononuclear phagocytes are often present in AMD lesions, but the processes that direct myeloid cell recruitment remain unclear. Here, we identify IL-33 as a key regulator of inflammation and photoreceptor degeneration after retina stress or injury. IL-33(+) Müller cells were more abundant and IL-33 cytokine was elevated in advanced AMD cases compared with age-matched controls with no AMD. In rodents, retina stress resulted in release of bioactive IL-33 that in turn increased inflammatory chemokine and cytokine expression in activated Müller cells. Deletion of ST2, the IL-33 receptor α chain, or treatment with a soluble IL-33 decoy receptor significantly reduced release of inflammatory mediators from Müller cells, inhibited accumulation of mononuclear phagocytes in the outer retina, and protected photoreceptor rods and cones after a retina insult. This study demonstrates a central role for IL-33 in regulating mononuclear phagocyte recruitment to the photoreceptor layer and positions IL-33 signaling as a potential therapeutic target in macular degenerative diseases.
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Hongkang
authors.initials: H
authors.lastname: Xi
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Katschke
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Tom
authors.initials: T
authors.lastname: Truong
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Linda
authors.initials: L
authors.lastname: Rangell
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Rommel
authors.initials: R
authors.lastname: Arceo
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hackney
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmacological Sciences, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmacological Sciences, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
authors.forename: Javier
authors.initials: J
authors.lastname: Cote-Sierra
authors.affiliation: Department of Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Justin
authors.initials: J
authors.lastname: Elstrott
authors.affiliation: Department of Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080 menno@gene.com.
authors.forename: Menno
authors.initials: M
authors.lastname: van Lookeren Campagne
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D063928:Ependymoglial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D066298:In Vitro Techniques; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008266:Macula Lutea / Q000276:immunology / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; C553108:Il33 protein, rat; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin