Toll-Like Receptor 4 Signaling in the Trabecular Meshwork

Abstract

Primary open-angle glaucoma is one of the leading causes of blindness worldwide. With limited therapeutics targeting the pathogenesis at the trabecular meshwork (TM), there is a great need for identifying potential new targets. Recent evidence has implicated Toll-like receptor 4 (TLR4) and it is signaling pathway in augmenting the effects of transforming growth factor beta-2 (TGFβ2) and downstream extracellular matrix production. In this review, we examine the role of TLR4 signaling in the trabecular meshwork and the interplay between endogenous activators of TLR4 (damage-associated molecular patterns (DAMPs)), extracellular matrix (ECM), and the effect on intraocular pressure.

Keywords: ECM; TLR4; glaucoma; intraocular pressure; trabecular meshwork.

FIGURE 1

TLR4 activation in the trabecular meshwork. In primary open-angle glaucoma, damage to the TM and inner wall of Schlemm’s canal (SC) endothelium prevents sufficient aqueous humor outflow leading to elevated IOP. Damage associated molecular patterns (DAMPs) such as cellular fibronectin containing EDA isoform (cFN-EDA) are produced from TM tissue damage and excess TGFβ2 signaling and can activate TLR4 leading to Nuclear Factor-Kappa Beta (NF-κB) activation and downregulation of BMP and Activin Membrane Bound Inhibitor (BAMBI) expression.

FIGURE 2

TLR4 and TGFβ2 signaling crosstalk. (A) The trabecular meshwork under homeostasis expresses basal levels of extracellular matrix proteins and BMP and Activin Membrane Bound Inhibitor (BAMBI), which inhibits endogenous TGFβ2 signaling. (B) Bioactivated TGFβ2 leads to the expression of DAMPs, including cFN-EDA and LMW Hyaluronic acid, which activate TLR4 and lead to subsequent NF-κB activation. Phosphorylated NF-κB lowers the expression of BAMBI, which in turn, leads to uninhibited TGFβ2 signaling.