The regulation of transforming growth factor beta-2-induced ocular hypertension and glaucomatous environment in the trabecular meshwork

Glaucoma is a heterogeneous group of optic neuropathies that damage the optic nerve that leads to progressive visual loss and irreversible blindness in over 80 million people worldwide. Primary open angle glaucoma (POAG) is the most common form of glaucoma, and elevated intraocular pressure (IOP) is the major risk factor for the development and progression of this ocular disease. One of the potential mechanisms responsible for elevated IOP in POAG patients is the excessive accumulation of extracellular matrix (ECM) proteins within the trabecular meshwork (TM). Damage to the TM impairs the aqueous humor outflow and increases aqueous humor outflow resistance, and elevates IOP. Discovering potential new disease modifying targets to lower IOP is necessary to develop effective therapies to inhibit the progression of glaucoma. Here, we explored a novel molecular mechanism involved in the development of glaucomatous TM ECM damage. The effects of transforming growth factor beta 2 (TGF[beta]2) signaling pathways in the TM ECM have been extensively studied. TGF[beta]2 is a profibrotic signaling component in ocular hypertension development that increases ECM deposition in the TM. As a member of the toll-like receptor family, toll-like receptor 4 (TLR4) was originally identified as the receptor for lipopolysaccharide (LPS). TLR4 can also be activated by endogenous ligands known as damaged associated molecular patterns (DAMPS), which are generated as a result of injury, cell damage, and ECM remodeling. DAMP-induced TLR4 activation has been linked to fibrosis, ECM protein deposition, and augmented TGF[beta]2 signaling and downstream fibrotic responses. Recently, we identified TGF[beta]2-TLR4 signaling crosstalk that regulates the TM ECM, and mutation in TLR4 rescues TGF[beta]2-induced ocular hypertension in mice. The goal of this work was to investigate the role of the endogenous TLR4 ligand fibronectin containing extra domain A isoform (FN-EDA), and the TLR4 downstream signaling molecule NF[kappa]B in TGF[beta]2-induced ocular hypertension in mice. Overall, we discovered that TLR4, FNEDA and NF[kappa]B are necessary for TGF[beta]2-induced ocular hypertension and ECM deposition in mice. In addition, constitutively active EDA mice spontaneously develop ocular hypertension. These data provide new targets to lower IOP and inhibit glaucoma disease progression.