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

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1866; no. 1; p. 165560
• Main Authors: Ho, Leona T.Y., Osterwald, Anja, Ruf, Iris, Hunziker, Daniel, Mattei, Patrizio, Challa, Pratap, Vann, Robin, Ullmer, Christoph, Rao, Ponugoti Vasanth
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2020
• Subjects: Animals; Aqueous humor; Aqueous Humor - metabolism; Autotaxin; Collagen Type I - metabolism; Connective Tissue Growth Factor - metabolism; Drainage - methods; Female; Fibronectins - metabolism; Glaucoma; Glaucoma - metabolism; Humans; Intraocular pressure; Intraocular Pressure - physiology; Lysophospholipids - metabolism; Male; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; Ocular Hypertension - metabolism; Phosphoric Diester Hydrolases - metabolism; Smad3 Protein - metabolism; Trabecular meshwork; Trabecular Meshwork - metabolism; POAG; Glaucoma; ATX; AH; IOP; Aqueous humor; IL-1β; CTGF; Trabecular meshwork; TNF-α; Autotaxin; TM; LPA; GAPDH; LPC; ERK; ELISA; Intraocular pressure
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.165560

Ocular hypertension due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM) is a major risk factor for glaucoma, a leading cause of irreversible blindness. However, the etiology of ocular hypertension remains unclear. Although autotaxin, a secreted lysophospholipase D and its catalytic product lysophosphatidic acid (LPA) have been shown to modulate AH drainage through TM, we do not have a complete understanding of their role and regulation in glaucoma patients, TM and AH outflow. This study reports a significant increase in the levels of autotaxin, lysophosphatidylcholine (LPC), LPA and connective tissue growth factor (CTGF) in the AH of Caucasian and African American open angle glaucoma patients relative to age-matched non-glaucoma patients. Treatment of human TM cells with dexamethasone, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) increased the levels of autotaxin protein, a response that was mitigated by inhibitors of glucocorticoid receptor, NF-kB and SMAD3. Dexamethasone, TNF-α, IL-1β and LPC treatment of TM cells also led to an increase in the levels of CTGF, fibronectin and collagen type 1 in an autotaxin dependent manner. Additionally, in perfused enucleated mouse eyes, autotaxin and LPC were noted to decrease, while inhibition of autotaxin was increased aqueous outflow through the TM. Taken together, these results provide additional evidence for dysregulation of the autotaxin-LPA axis in the AH of glaucoma patients, reveal molecular insights into the regulation of autotaxin expression in TM cells and the consequences of autotaxin inhibitors in suppressing the fibrogenic response and resistance to AH outflow through the TM. •AH derived from the POAG patients contains elevated levels of ATX, LPA and LPC.•Dexamethasone, TNFα and IL-1β increase ATX protein levels in TM cells.•ATX plays a crucial role in dexamethasone, TNFα and IL-1β induced fibrogenic response in TM cells.•LPC induces fibrogenic response in TM cells in an ATX-dependent manner.•ATX inhibitor increases aqueous outflow facility in mouse eyes.