title: NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components.
abstract: Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1b (IL-1b) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress-related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD–like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3(-/-) but not Il1r1(-/-) mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Doyle
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.forename: Ema
authors.initials: E
authors.lastname: Ozaki
authors.forename: Robert G
authors.initials: RG
authors.lastname: Salomon
authors.forename: Andres
authors.initials: A
authors.lastname: Mori
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kenna
authors.forename: Gwyneth Jane
authors.initials: GJ
authors.lastname: Farrar
authors.forename: Anna-Sophia
authors.initials: AS
authors.lastname: Kiang
authors.forename: Marian M
authors.initials: MM
authors.lastname: Humphries
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.forename: Joe G
authors.initials: JG
authors.lastname: Hollyfield
authors.forename: Peter
authors.initials: P
authors.lastname: Humphries
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000209:etiology / Q000517:prevention & control; D015922:Complement C1q / Q000502:physiology; D007114:Immunization; D020382:Interleukin-18 / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D008268:Macular Degeneration / Q000517:prevention & control*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015594:Optic Disk Drusen / Q000378:metabolism*; D010588:Phagosomes / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D015922:Complement C1q