title: Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.
abstract: Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. Inflammasome inhibition attenuated photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.
authors.affiliation: 1] Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA [2] Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Notomi
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Sweigard
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Atik
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Connor
authors.affiliation: Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Terasaki
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Vavvas
mesh_terms: D000368:Aged; D000818:Animals; D016923:Cell Death / Q000502:physiology; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D012163:Retinal Detachment / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse