Intraocular iron injection induces oxidative stress followed by elements of geographic atrophy and sympathetic ophthalmia.

Animals Disease Models, Animal Ferric Compounds / administration & dosage Geographic Atrophy / chemically induced Injections, Intraocular / methods Iron / metabolism Male Mice Mice, Inbred C57BL Ophthalmia, Sympathetic / chemically induced Optical Imaging / methods Oxidative Stress / drug effects Quaternary Ammonium Compounds / administration & dosage Retinal Pigment Epithelium / diagnostic imaging
iron lipid peroxidation lipofuscin oxidative stress photoreceptor cells

Journal

Aging cell
ISSN: 1474-9726
Titre abrégé: Aging Cell
Pays: England
ID NLM: 101130839

Informations de publication

Date de publication:
11 2021
Historique:
revised: 24 08 2021
received: 04 06 2021
accepted: 14 09 2021
pubmed: 10 10 2021
medline: 26 2 2022
entrez: 9 10 2021
Statut: ppublish

Résumé

Iron has been implicated in the pathogenesis of age-related retinal diseases, including age-related macular degeneration (AMD). Previous work showed that intravitreal (IVT) injection of iron induces acute photoreceptor death, lipid peroxidation, and autofluorescence (AF). Herein, we extend this work, finding surprising chronic features of the model: geographic atrophy and sympathetic ophthalmia. We provide new mechanistic insights derived from focal AF in the photoreceptors, quantification of bisretinoids, and localization of carboxyethyl pyrrole, an oxidized adduct of docosahexaenoic acid associated with AMD. In mice given IVT ferric ammonium citrate (FAC), RPE died in patches that slowly expanded at their borders, like human geographic atrophy. There was green AF in the photoreceptor ellipsoid, a mitochondria-rich region, 4 h after injection, followed later by gold AF in rod outer segments, RPE and subretinal myeloid cells. The green AF signature is consistent with flavin adenine dinucleotide, while measured increases in the bisretinoid all-trans-retinal dimer are consistent with the gold AF. FAC induced formation carboxyethyl pyrrole accumulation first in photoreceptors, then in RPE and myeloid cells. Quantitative PCR on neural retina and RPE indicated antioxidant upregulation and inflammation. Unexpectedly, reminiscent of sympathetic ophthalmia, autofluorescent myeloid cells containing abundant iron infiltrated the saline-injected fellow eyes only if the contralateral eye had received IVT FAC. These findings provide mechanistic insights into the potential toxicity caused by AMD-associated retinal iron accumulation. The mouse model will be useful for testing antioxidants, iron chelators, ferroptosis inhibitors, anti-inflammatory medications, and choroidal neovascularization inhibitors.

Identifiants

DOI: 10.1111/acel.13490 PMID: 34626070 PMC: PMC8590099
pubmed: 34626070
doi: 10.1111/acel.13490
pmc: PMC8590099
doi:

Substances chimiques

Ferric Compounds 0
Quaternary Ammonium Compounds 0
Iron E1UOL152H7
ferric ammonium citrate UVP74NG1C5

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e13490

Subventions

Organisme : NIH HHS
ID : S10 OD026860
Pays : United States
Organisme : NIH HHS
ID : EY028916
Pays : United States
Organisme : NIH HHS
ID : EY015240
Pays : United States
Organisme : NEI NIH HHS
ID : F30 EY032339
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY019007
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028916
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY015240
Pays : United States
Organisme : NIH HHS
ID : S10OD026860
Pays : United States
Organisme : NIH HHS
ID : EY028131
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY001583
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028131
Pays : United States

Informations de copyright

© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

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Auteurs

Yingrui Liu (Y)

Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
ORCID: 0000-0002-6652-5358

Brent A Bell (BA)

F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Ying Song (Y)

F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Hye J Kim (HJ)

Department of Ophthalmology, Harkness Eye Institute, Columbia University Medical Center, New York, New York, USA.

Jacob K Sterling (JK)

F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Benjamin J Kim (BJ)

Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Maura Poli (M)

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Michelle Guo (M)

F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Kevin Zhang (K)

F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Aditya Rao (A)

Department of Molecular Life Science, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Janet R Sparrow (JR)

Department of Ophthalmology, Harkness Eye Institute, Columbia University Medical Center, New York, New York, USA.

Guanfang Su (G)

Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.

Joshua L Dunaief (JL)

F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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Classifications MeSH

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