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.
Highlights
Glaucoma is a heterogeneous group of optic neuropathies with progressive degeneration of the optic nerve leading to vision loss and irreversible blindness[1]
We discovered that fibronectin extra domain A (EDA) (FN-EDA) enhances the TGFβ2-induced extracellular matrix (ECM) response in primary trabecular meshwork (TM) cells, and this effect can be blocked by inhibition of toll-like receptor 4 (TLR4) signaling[15]
We showed that FN containing the EDA isoform can increase ECM production and enhance the effects of TGFβ2 in primary human TM cells in culture, and this effect could be blocked by inhibition of TLR415
Summary
Glaucoma is a heterogeneous group of optic neuropathies with progressive degeneration of the optic nerve leading to vision loss and irreversible blindness[1]. The pathology of the disease is well studied, many of the current drug therapies used to lower elevated IOP focus on suppressing the aqueous humor formation and enhancing uveoscleral outflow; these particular therapies do not target the molecular pathology of the disease at the TM. Many of these therapies are not uniformly effective, can progressively lose efficacy, and only slow vision loss progression[21]. We discovered that FN-EDA enhances the TGFβ2-induced ECM response in primary TM cells, and this effect can be blocked by inhibition of toll-like receptor 4 (TLR4) signaling[15]. We identify the importance of FN-EDA in the development of ocular hypertension using transgenic mice that either constitutively express the EDA isoform or contain an EDA null copy, with or without knockdown of Tlr[4]
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