title: DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.
abstract: Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, 40506, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirano
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.forename: Sami
authors.initials: S
authors.lastname: Dridi
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kim
authors.forename: Won Gil
authors.initials: WG
authors.lastname: Cho
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fowler
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.forename: Romulo J C
authors.initials: RJ
authors.lastname: Albuquerque
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Kugel
authors.forename: James A
authors.initials: JA
authors.lastname: Goodrich
authors.forename: Steven L
authors.initials: SL
authors.lastname: Ponicsan
authors.forename: Gautam
authors.initials: G
authors.lastname: Chaudhuri
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Yoo
authors.forename: Dong-ki
authors.initials: DK
authors.lastname: Lee
authors.forename: Patrick
authors.initials: P
authors.lastname: Provost
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.forename: Judit Z
authors.initials: JZ
authors.lastname: Baffi
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D020087:Alu Elements; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D057092:Geographic Atrophy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D043244:Ribonuclease III / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D051193:Toll-Like Receptors; C408087:DICER1 protein, human; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases