Role of the autotaxin-lysophosphatidic acid axis in glaucoma, aqueous humor drainage and fibrogenic activity

Ho, Leona; Osterwald, Anja; Ruf, Iris; Hunziker, Daniel; Mattei, Patrizio; Challa, Pratap; Vann, Robin; Ullmer, Christoph; Rao, P.V.

doi:10.1016/j.bbadis.2019.165560

Cited by 38 publications

(51 citation statements)

References 46 publications

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“…24,32,69,70 Therefore, determining downstream targets on which these pathways converge may enhance effective and efficient blockade of attendant/accompanying fibrotic phenotypes associated with elevated IOP. Consequently, in this study, for the first time, we show that LPA, which is elevated in the aqueous humor of patients with POAG, 40 and IL6 trans-signaling (relevant because sIL6R is elevated in the aqueous humor of patients with POAG as well) 32 interact via YAP, TAZ, and pSTAT3 signaling molecules to precipitate ocular hypertensive phenotypes in hTM cells ( Fig. 11; left cellular compartment).…”

Section: Discussionmentioning

confidence: 60%

“…62,63,73 For instance, ROCK1 is the target of a relatively new class of IOP-lowering medications that inhibit increased contractility to "relax" noncompliant hTM cells. 10 Furthermore, overexpression of intracellular and extracellular fibrotic phenotypes like α-SMA, collagens I and IV, fibronectin, laminin, CYR61, and CTGF implicated in endoplasmic reticulum (ER) stress, elevated IOP, and glaucoma 28,40,[74][75][76][77][78][79] were observed. For instance, increased deposition of fibronectin is associated with ER stress, 76 and is necessary for the assembly/maturation of other ECM proteins like collagen IV, fibrillin and laminin, 15 which may contribute to altered tissue biomechanics.…”

Section: Discussionmentioning

confidence: 99%

“…30 Moreover, perfusion of LPA or ATX in porcine or mice anterior segment organ cultures ex vivo decreases aqueous outflow facility, whereas inhibition of ATX increases aqueous outflow. 29,40 The desired outcome of LPA's or ATX's inhibition on outflow facility is associated with decreases in actin stress fibers, focal adhesions, and myosin light chain phosphorylation. 30,31,33 More recently, the well-established mechanotransducers, Yes-associated protein (YAP) and Transcriptional coactivator with a PDZ-binding motif (TAZ), [41][42][43][44] have been identified as key downstream mediators of LPAinduced increased cell contractility and ECM deposition.…”

mentioning

confidence: 99%

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Lysophosphatidic Acid and IL-6 Trans-signaling Interact via YAP/TAZ and STAT3 Signaling Pathways in Human Trabecular Meshwork Cells

Yemanyi

Raghunathan

2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Lysophosphatidic acid (LPA) and soluble interleukin-6 receptor (sIL6R) are elevated in primary open angle glaucoma (POAG). LPA and IL6 modulate in response to biomechanical stimuli and converge on similar fibrotic phenotypes. Thus, we determined whether LPA and IL6 trans-signaling (IL6/sIL6R) interact via Yes-associated protein (YAP)/Transcriptional coactivator with a PDZ-binding motif (TAZ) or Signal transducer and activator of transcription 3 (STAT3) pathways in human trabecular meshwork (hTM) cells. METHODS. Confluent primary hTM cells were serum starved for 24 hours, and treated with vehicle, LPA (20 μM), IL6 (100 ng/mL)/sIL6R (200 ng/mL), or both (LPA + IL6/sIL6R) for 24 hours, with or without a YAP inhibitor (verteporfin; 2 μM) or STAT3 inhibitor (2 μM). Expression of key receptors and ligands, signaling mediators, actomyosin machinery, cell contractility, and extracellular matrix (ECM) targets of both signaling pathways was determined by immunocytochemistry, RT-qPCR, and Western blotting. RESULTS. LPA and IL6 trans-signaling coupling overexpressed/activated receptors and ligands, glycoprotein-130, IL6, and autotaxin; signaling mediators, YAP, TAZ, Pan-TEAD, and phosphorylated STAT3 (pSTAT3); actomyosin and contractile machinery components, myosin light chain 2 (MLC2), phosphorylated MLC2, rho-associated protein kinase 1, filamentous actin, and α-smooth muscle actin; and fibrotic ECM proteins, collagen I and IV, fibronectin, laminin, cysteine-rich angiogenic inducer 61, and connective tissue growth factor in hTM cells; mostly beyond LPA or IL6 trans-signaling alone. Verteporfin inhibited YAP, TAZ, and pSTAT3, with concomitant abrogation of aforementioned fibrotic targets; the STAT3 inhibitor was only partially effective. CONCLUSIONS. These data suggest synergistic crosstalk between LPA and IL6 transsignaling, mediated by YAP, TAZ, and pSTAT3. By completely inhibiting these mediators, verteporfin may be more efficacious in ameliorating LPA and/or IL6 trans-signalinginduced ocular hypertensive phenotypes in hTM cells.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Lysophosphatidic Acid and IL-6 Trans-signaling Interact via YAP/TAZ and STAT3 Signaling Pathways in Human Trabecular Meshwork Cells

Yemanyi

Raghunathan

2020

Invest. Ophthalmol. Vis. Sci.

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“…These data emphasize the important contractile connection between the ciliary muscle and TM. Unexpectedly, autotaxin (gene name: ENPP2) which been shown to be elevated in aqueous humor of glaucoma patients (50,51) was expressed in scleral spur/ Schwann cell like cluster and melanocyte cell clusters, but not TM1 or TM2. This is in contrast to previous reports finding autotaxin protein in human TM specimens(73).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, CAV1 and CAV2 were expressed at low levels in TM1 and TM2, but highly expressed in lymphatic-vascular endothelia cell cluster. Autotaxin (gene name: ENPP2) has been shown to be elevated in aqueous humor of glaucoma patients (50,51) and studies have shown that autotaxin inhibitors lower IOP in mice and rabbits (50,52). In the outflow transcriptome, ENPP2 was expressed in schwann cell like and melanocyte cell clusters ( Figure 9C).…”

Section: Cell Type Specific Expression Of Glaucoma-related Genesmentioning

confidence: 99%

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

Patel

Fury

Yang

et al. 2020

Preprint

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The conventional outflow pathway is a complex tissue responsible for maintaining intraocular pressure (IOP) homeostasis. The coordinated effort of multiple cells with differing responsibilities ensure healthy outflow function and IOP maintenance. Dysfunction of one or more resident cell type results in ocular hypertension and risk for glaucoma, a leading cause of blindness. In this study, single cell RNA sequencing was performed to generate a comprehensive cell atlas of human conventional outflow tissues. We obtained 17757 genes expression profiles from 8758 cells from eight eyes of four donors representing the outflow cell transcriptome. Upon clustering analysis, 12 distinct cell types were identified, and region-specific expression of candidate genes were mapped in human tissues. Significantly, we identified two distinct expression patterns (myofibroblast and fibroblast) from cells located in the trabecular meshwork (TM), the primary structural component of the conventional outflow pathway. We also located neuron and macrophage signatures in the TM.The second primary component structure, Schlemm's canal displayed a unique combination of lymphatic/blood vascular gene expression. Other expression clusters corresponded to cells from neighboring tissues, predominantly in the ciliary muscle/scleral spur, which together correspond to the uveoscleral outflow path. Importantly, the utility of our atlas was demonstrated by mapping glaucomarelevant genes to outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of conventional and unconventional outflow pathway structures responsible for IOP homeostasis. Significance statementOcular hypertension is the primary, and only modifiable risk factor for glaucoma, the leading cause of irreversible blindness. Intraocular pressure is regulated homeostatically by resistance to aqueous humor outflow through an architecturally complex tissue, the conventional/trabecular pathway. In this study, we generated a comprehensive cell atlas of the human trabecular meshwork and neighboring tissues using single cell, RNA sequencing. We identified 12 distinct cell types, and mapped regionspecific expression of candidate genes. The utility of our atlas was demonstrated by mapping glaucoma-relevant genes to conventional outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of tissue structures responsible for intraocular pressure homeostasis in health, and dysregulation in disease.

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CCN2/CTGF promotor activity in the developing and adult mouse eye

et al. 2021

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CCN2/CTGF is a matricellular protein that is known to enhance transforming growth factor-β signaling and to induce a myofibroblast-like phenotype in a variety of cell types. Here, we investigated Ccn2/Ctgf promotor activity during development and in the adult mouse eye, using CTGFLacZ/+ mice in which the β-galactosidase reporter gene LacZ had been inserted into the open reading frame of Ccn2/Ctgf. Promotor activity was assessed by staining for β-galactosidase activity and by immunolabeling using antibodies against β-galactosidase. Co-immunostaining using antibodies against glutamine synthetase, glial fibrillary acidic protein, choline acetyltransferase, and CD31 was applied to identify specific cell types. Ccn2/Ctgf promotor activity was intense in neural crest-derived cells differentiating to corneal stroma and endothelium, and to the stroma of choroid, iris, ciliary body, and the trabecular meshwork during development. In the adult eye, a persistent and very strong promotor activity was present in the trabecular meshwork outflow pathways. In addition, endothelial cells of Schlemm’s canal, and of retinal and choroidal vessels, retinal astrocytes, Müller glia, and starburst amacrine cells were stained. Very strong promoter activity was seen in the astrocytes of the glial lamina at the optic nerve head. We conclude that CCN2/CTGF signaling is involved in the processes that govern neural crest morphogenesis during ocular development. In the adult eye, CCN2/CTGF likely plays an important role for the trabecular meshwork outflow pathways and the glial lamina of the optic nerve head.

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Role of the autotaxin-lysophosphatidic acid axis in glaucoma, aqueous humor drainage and fibrogenic activity

Cited by 38 publications

References 46 publications

Lysophosphatidic Acid and IL-6 Trans-signaling Interact via YAP/TAZ and STAT3 Signaling Pathways in Human Trabecular Meshwork Cells

Lysophosphatidic Acid and IL-6 Trans-signaling Interact via YAP/TAZ and STAT3 Signaling Pathways in Human Trabecular Meshwork Cells

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

CCN2/CTGF promotor activity in the developing and adult mouse eye

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