Autophagy modulation in animal models of corneal diseases: a systematic review

Abstract

Autophagy is an intracellular catabolic process implicated in the recycling and degradation of intracellular components. Few studies have defined its role in corneal pathologies. Animal models are essential for understanding autophagy regulation and identifying new treatments to modulate its effects. A systematic review (SR) was conducted of studies employing animal models for investigations of autophagy in corneal diseases. Studies were identified using a structured search strategy (TS = autophagy AND cornea*) in Web of Science, Scopus, and PubMed from inception to September 2019. In this study, 230 articles were collected, of which 28 were analyzed. Mouse models were used in 82% of the studies, while rat, rabbit, and newt models were used in the other 18%. The most studied corneal layer was the epithelium, followed by the endothelium and stroma. In 13 articles, genetically modified animal models were used to study Fuch endothelial corneal dystrophy (FECD), granular corneal dystrophy type 2 (GCD2), dry eye disease (DED), and corneal infection. In other 13 articles, animal models were experimentally induced to mimic DED, keratitis, inflammation, and surgical scenarios. Furthermore, in 50% of studies, modulators that activated or inhibited autophagy were also investigated. Protective effects of autophagy activators were demonstrated, including rapamycin for DED and keratitis, lithium for FECD, LYN-1604 for DED, cysteamine and miR-34c antagomir for damaged corneal epithelium. Three autophagy suppressors were also found to have therapeutic effects, such as aminoimidazole-4-carboxamide-riboside (AICAR) for corneal allogeneic transplantation, celecoxib and chloroquine for DED.

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Abbreviations

AICAR:

Aminoimidazole-4-carboxamide riboside

AMD:

Age-related macular degeneration

AMPK:

AMP-activated protein kinase

ATGs:

Autophagy-related

BBD:

Beclin-binding domain

BECN1:

Beclin-1

COX:

Cyclooxygenase

CsA:

Cyclosporine A

DC:

Dendritic cells

DED:

Dry eye disease

DDIT4:

DNA damage-inducible transcript 4

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assay

ER:

Endoplasmic reticulum

ERK:

Extracellular signal regulated kinase

FECD:

Fuch endothelial corneal dystrophy

FoxO3:

Forkhead box O3

FYCO1:

Coiled-coil domain containing 1

GCD2:

Granular corneal dystrophy type 2

GFAP:

Glial fibrillary acidic protein

H&E:

Hematoxylin–eosin

HCEC:

Human corneal epithelial cells

HIF-1α:

Hypoxia-inducible factor

HSK:

Herpetic stromal keratitis

HSV-1:

Herpes simplex virus

ICNs:

Intraepithelial corneal nerves

IFNγ:

Gamma interferon

IL:

Interleukin

IMPase:

Inositol monophosphatase

INT:

Intraepithelial nerve terminal

IRF3:

IFN regulatory factor 3

LAMP:

Lysosomal-associated membrane protein

LYVE-1:

Lymphatic vascular endothelial gene

MAP1LC3:

Microtubule-associated protein 1 light chain 3

MHCII:

Histocompatibility complex class II

MMC:

Mitomycin-C

mTOR:

Mammalian target of rapamycin

mTORC1:

Mammalian target of rapamycin complex

NAC:

N-acetylcysteine

NO:

Nitric oxide

NOD:

Non-obese diabetic

NOX4:

Nicotinamide adenine dinucleotide phosphate oxidase 4

MMP:

Matrix metalloproteinase

PAS:

Periodic acid Schiff

PDGFR:

Platelet-derived growth factor receptors

PECAM:

Platelet endothelial cell adhesion molecule

PI3KC3, also known as VPS34:

Phosphatidylinositol 3-kinase, catalytic subunit type 3

PI3P:

Phosphatidylinositol 3-phosphate

PI3K:

Phosphatidylinositol-3-kinase

PRISMA:

Preferred Reporting Items for Systematic reviews and Meta-Analysis

PROSPERO:

Prospective Register of Systematic Reviews

PrP:

Protein prion

PUMA:

P53 upregulated modulator of apoptosis

qPCR:

Quantitative polymerase chain reaction

ROCK:

Rho-associated protein kinase

ROS:

Reactive oxygen species

RPE:

Retinal pigmented epithelium

SiNPs:

Nonporous silica nanoparticles

Sirt3:

Silent mating type information regulation 2 homolog 3

SR:

Systematic review

SYRCLE’s:

Systematic Review Center for Laboratory Animal Experimentation’s

TFEB:

Transcription factor EB

TGFB1:

Transforming growth factor beta 1

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

TNF:

Tumor necrosis factor

TSC:

Tuberous Sclerosis Complex

ULK1:

UNC-51-like kinase

UPR:

Unfolded protein response

UPS:

Ubiquitin–proteasome system

VEGF:

Vascular endothelial growth factor

3-MA:

3-Methyladenine

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Acknowledgements

The systematic review was performed at the Jesús Usón Minimally Invasive Surgery Center (CCMIJU) which is part of the ICTS “Nanbiosis.” G.MC was supported by ONCE Foundation. F.J. Vela, J.L. Campos, E. Abellán and A. Ballestín were supported by Jesús Usón Minimally Invasive Surgery Foundation. S.M.S. Y-D was supported by Isabel Gemio Foundation. Authors thank Raquel Lozano Delgado for the illustration of the Fig. 2. Autophagy modulators targeting different steps of the autophagic machinery in corneal diseases, and FUNDESALUD for helpful assistance.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Martínez-Chacón, G., Vela, F.J., Campos, J.L. et al. Autophagy modulation in animal models of corneal diseases: a systematic review. Mol Cell Biochem 474, 41–55 (2020). https://doi.org/10.1007/s11010-020-03832-5

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Keywords

  • Autophagy
  • Animal model
  • Corneal disease
  • PRISMA
  • Systematic review