Tasneem P Sharma1, Stacy Curry1, Colleen M McDowell2. 1. Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas. 2. Department of Ophthalmology and Visual Sciences, McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, Wisconsin.
Abstract
Purpose: Transforming growth factor-β2 (TGFβ2) and Toll-like receptor 4 (TLR4) crosstalk have been implicated in extracellular matrix regulation in the trabecular meshwork (TM) and ocular hypertension in mice. We investigated TLR4 expression in normal and glaucomatous human trabecular meshwork (HTM) sections and utilized a human perfusion organ culture model to determine TGFβ2-TLR4 signaling crosstalk in glaucoma. Methods: Expression of TLR4 was determined in TM of normal and glaucomatous human eyes. Anterior segments of paired human eyes were perfused at a constant flow rate (2.5 μL/min) for 4 days to acquire stable baseline intraocular pressures (IOPs). We treated paired eyes with two different treatment paradigms: (1) TGFβ2 in one eye and vehicle control in the paired eye, (2) TGFβ2 in one eye and TGFβ2 + TLR4 inhibitor TAK-242 in the paired eye. Perfusate and TM tissue were collected and analyzed for fibronectin (FN) and collagen IV (COLIV) expression. Results: We observed increased TLR4 expression in glaucomatous HTM sections compared to normal (age-matched) (P < 0.05). Significant elevation of IOP was detected in 47% of TGFβ2-treated anterior segments (P < 0.01) compared to control, and in TGFβ2 treated compared with co-treatment with TGFβ2 + TLR4 inhibitor (P < 0.0001). An increase in FN and COLIV expression was observed after TGFβ2 treatment, and inhibition of TLR4 signaling decreased TGFβ2-induced FN and COLIV expression in perfusate (P < 0.05). Conclusions: These studies identify TGFβ2-TLR4 crosstalk as a novel pathway in glaucoma. They provide a potential new target to lower IOP and explore glaucoma pathogenesis.
Purpose: Transforming growth factor-β2 (TGFβ2) and Toll-like receptor 4 (TLR4) crosstalk have been implicated in extracellular matrix regulation in the trabecular meshwork (TM) and ocular hypertension in mice. We investigated TLR4 expression in normal and glaucomatoushuman trabecular meshwork (HTM) sections and utilized a human perfusion organ culture model to determine TGFβ2-TLR4 signaling crosstalk in glaucoma. Methods: Expression of TLR4 was determined in TM of normal and glaucomatous human eyes. Anterior segments of paired human eyes were perfused at a constant flow rate (2.5 μL/min) for 4 days to acquire stable baseline intraocular pressures (IOPs). We treated paired eyes with two different treatment paradigms: (1) TGFβ2 in one eye and vehicle control in the paired eye, (2) TGFβ2 in one eye and TGFβ2 + TLR4 inhibitor TAK-242 in the paired eye. Perfusate and TM tissue were collected and analyzed for fibronectin (FN) and collagen IV (COLIV) expression. Results: We observed increased TLR4 expression in glaucomatous HTM sections compared to normal (age-matched) (P < 0.05). Significant elevation of IOP was detected in 47% of TGFβ2-treated anterior segments (P < 0.01) compared to control, and in TGFβ2 treated compared with co-treatment with TGFβ2 + TLR4 inhibitor (P < 0.0001). An increase in FN and COLIV expression was observed after TGFβ2 treatment, and inhibition of TLR4 signaling decreased TGFβ2-induced FN and COLIV expression in perfusate (P < 0.05). Conclusions: These studies identify TGFβ2-TLR4 crosstalk as a novel pathway in glaucoma. They provide a potential new target to lower IOP and explore glaucoma pathogenesis.
Authors: Swati Bhattacharyya; Kathleen Kelley; Denisa S Melichian; Zenshiro Tamaki; Feng Fang; Yunyun Su; Gilbert Feng; Richard M Pope; G R Scott Budinger; Gökhan M Mutlu; Robert Lafyatis; Timothy Radstake; Carol Feghali-Bostwick; John Varga Journal: Am J Pathol Date: 2012-11-07 Impact factor: 4.307
Authors: Ekihiro Seki; Samuele De Minicis; Christoph H Osterreicher; Johannes Kluwe; Yosuke Osawa; David A Brenner; Robert F Schwabe Journal: Nat Med Date: 2007-10-21 Impact factor: 53.440
Authors: Algis Grybauskas; Tomoyo Koga; Paulius V Kuprys; Michael Nolan; Ryan McCarty; Loyal Walker; Kelsey A Green; William M Norkett; Beatrice Y J T Yue; Paul A Knepper Journal: Mol Vis Date: 2015-03-05 Impact factor: 2.367
Authors: Amanda L Roberts; Timur A Mavlyutov; Tanisha E Perlmutter; Stacy M Curry; Sherri L Harris; Anil K Chauhan; Colleen M McDowell Journal: Sci Rep Date: 2020-06-17 Impact factor: 4.379