Crosstalk Between Transforming Growth Factor Beta-2 and Toll-Like Receptor 4 in the Trabecular Meshwork

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dc.creatorHernandez, Humberto
dc.creatorMedina-Ortiz, Wanda E.
dc.creatorLuan, Tomi
dc.creatorClark, Abbot F.
dc.creatorMcDowell, Colleen M.
dc.creator.orcid0000-0003-3594-6560 (Clark, Abbot F.)
dc.date.accessioned2022-09-13T16:34:17Z
dc.date.available2022-09-13T16:34:17Z
dc.date.issued2022-03
dc.description.abstractPurpose: The trabecular meshwork (TM) is involved in the outflow of aqueous humor and intraocular pressure (IOP) regulation. Regulation of the extracellular matrix (ECM) by TGFbeta2 signaling pathways in the TM has been extensively studied. Recent evidence has implicated toll-like receptor 4 (TLR4) in the regulation of ECM and fibrogenesis in liver, kidney, lung, and skin. Here, we investigated the role of TGFbeta2-TLR4 signaling crosstalk in the regulation of the ECM in the TM and ocular hypertension. Methods: Cross sections of human donor eyes, primary human TM cells in culture, and dissected mouse TM rings were used to determine Tlr4 expression in the TM. Trabecular meshwork cells in culture were treated with TGFbeta2 (5 ng/mL), TLR4 inhibitor (TAK-242, 15 muM), and a TLR4 ligand (cellular fibronectin isoform [cFN]-EDA). A/J (n = 13), AKR/J (n = 7), BALBc/J (n = 8), C3H/HeJ (n = 20), and C3H/HeOuJ (n = 10) mice were injected intravitreally with adenovirus 5 (Ad5).hTGFbeta2c226s/c228s in one eye, with the uninjected contralateral eye serving as a control. Conscious IOP measurements were taken using a TonoLab rebound tonometer. Results: Toll-like receptor 4 is expressed in the human and mouse TM. Inhibition of TLR4 signaling in the presence of TGFbeta2 decreases fibronectin expression. Activation of TLR4 by cFN-EDA in the presence of TGFbeta2 further increases fibronectin, laminin, and collagen-1 expression, and TLR4 signaling inhibition blocks this effect. Ad5.hTGFbeta2c226s/c228s induces ocular hypertension in wild-type mice but has no effect in Tlr4 mutant (C3H/HeJ) mice. Conclusions: These studies identify TGFbeta2-TLR4 crosstalk as a novel pathway involved in ECM regulation in the TM and ocular hypertension. These data further explain the complex mechanisms involved in the development of glaucomatous TM damage.
dc.description.sponsorshipSupported by Bright Focus Foundation G2014063 (CMM), National Institutes of Health Grant R01EY026529 (CMM), and Neurobiology of Aging Training Grant T32AG020494 (HH).
dc.identifier.citationHernandez, H., Medina-Ortiz, W. E., Luan, T., Clark, A. F., & McDowell, C. M. (2017). Crosstalk Between Transforming Growth Factor Beta-2 and Toll-Like Receptor 4 in the Trabecular Meshwork. Investigative ophthalmology & visual science, 58(3), 1811-1823. https://doi.org/10.1167/iovs.16-21331
dc.identifier.issn1552-5783
dc.identifier.issue3
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31725
dc.identifier.volume58
dc.publisherARVO Journals
dc.relation.urihttps://doi.org/10.1167/iovs.16-21331
dc.rights.holderCopyright 2017 The Authors
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceInvestigative Ophthalmology & Visual Science
dc.subject.meshAnimals
dc.subject.meshAqueous Humor / metabolism
dc.subject.meshBlotting, Western
dc.subject.meshCells, Cultured
dc.subject.meshGene Expression Regulation
dc.subject.meshHumans
dc.subject.meshImmunohistochemistry
dc.subject.meshIntraocular Pressure
dc.subject.meshMice
dc.subject.meshMice, Inbred AKR
dc.subject.meshMice, Inbred C3H
dc.subject.meshOcular Hypertension / genetics
dc.subject.meshOcular Hypertension / metabolism
dc.subject.meshOcular Hypertension / pathology
dc.subject.meshRNA / genetics
dc.subject.meshReal-Time Polymerase Chain Reaction
dc.subject.meshSignal Transduction
dc.subject.meshToll-Like Receptor 4 / biosynthesis
dc.subject.meshToll-Like Receptor 4 / genetics
dc.subject.meshTrabecular Meshwork / metabolism
dc.subject.meshTrabecular Meshwork / pathology
dc.subject.meshTransforming Growth Factor beta2 / biosynthesis
dc.subject.meshTransforming Growth Factor beta2 / genetics
dc.titleCrosstalk Between Transforming Growth Factor Beta-2 and Toll-Like Receptor 4 in the Trabecular Meshwork
dc.typeArticle
dc.type.materialtext

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