Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling

Amanda L Roberts; Timur A Mavlyutov; Tanisha E Perlmutter; Stacy M Curry; Sherri L Harris; Anil K Chauhan; Colleen M McDowell

doi:10.1038/s41598-020-66756-6

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Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling

Journal article

Open access

Peer reviewed

Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling

Amanda L Roberts, Timur A Mavlyutov, Tanisha E Perlmutter, Stacy M Curry, Sherri L Harris, Anil K Chauhan and Colleen M McDowell

Scientific reports, Vol.10(1), pp.9815-9815

06/17/2020

DOI: 10.1038/s41598-020-66756-6

PMCID: PMC7299944

PMID: 32555351

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Abstract

Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma and is due to trabecular meshwork (TM) damage, which leads to impaired aqueous humor outflow. Here, we explore a novel molecular mechanism involved in glaucomatous TM damage. We investigated the role of an endogenous Toll-like receptor 4 (TLR4) ligand, fibronectin-EDA (FN-EDA), in TGFβ2-induced ocular hypertension in mice. We utilized transgenic mouse strains that either constitutively express only FN containing the EDA isoform or contain an EDA-null allele and express only FN lacking EDA, with or without a mutation in Tlr4, in our inducible mouse model of ocular hypertension by injection of Ad5.TGFβ2. IOP was measured over time and eyes accessed by immunohistochemistry for total FN and FN-EDA expression. Constitutively active EDA caused elevated IOP starting at 14 weeks of age. Ad5.TGFβ2 induced ocular hypertension in wildtype C57BL/6J mice and further amplified the IOP in constitutively active EDA mice. TLR4 null and EDA null mice blocked Ad5.TGFβ-induced ocular hypertension. Total FN and FN-EDA isoform expression increased in response to Ad5.TGFβ2. These data suggest that both TLR4 and FN-EDA contribute to TGFβ2 induced ocular hypertension.

Animals

Fibronectins - chemistry

Fibronectins - metabolism

Gene Expression Regulation

Intraocular Pressure

Mice

Mice, Inbred C57BL

Signal Transduction

Toll-Like Receptor 4 - metabolism

Trabecular Meshwork - cytology

Trabecular Meshwork - metabolism

Transforming Growth Factor beta2 - metabolism

Details

Title: Subtitle: Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling
Creators: Amanda L Roberts - University of North Texas Health Science Center
Timur A Mavlyutov - University of Wisconsin–Madison
Tanisha E Perlmutter - University of Wisconsin–Madison
Stacy M Curry - University of North Texas Health Science Center
Sherri L Harris - University of North Texas Health Science Center
Anil K Chauhan - University of Iowa
Colleen M McDowell - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: Scientific reports, Vol.10(1), pp.9815-9815
DOI: 10.1038/s41598-020-66756-6
PMID: 32555351
PMCID: PMC7299944
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: P30 EY016665 / NEI NIH HHS R01 HL118742 / NHLBI NIH HHS R35 HL139926 / NHLBI NIH HHS U01 NS113388 / NINDS NIH HHS R01 NS109910 / NINDS NIH HHS R01 EY026529 / NEI NIH HHS R25 GM125587 / NIGMS NIH HHS R01 HL118246 / NHLBI NIH HHS
Language: English
Date published: 06/17/2020
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359561902771

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