On the role of innate immune Toll-like receptor 4 in primary open-angle glaucoma
Primary open-angle glaucoma (POAG) is a progressive optic neuropathy characterized by degeneration of retinal ganglion cell (RGC) axons and RGC death. Current treatments for POAG rely on the control of intraocular pressure (IOP); however, this strategy is not always sufficient to prevent progression of the disease. Increasing evidence suggests that the pathophysiology of POAG is complex and depends on multiple interacting factors including IOP, the immune system, the vascular system, and genetic and epigenetic alterations. One connection that can be made between each of these factors is the influence of innate immune receptor Toll-like receptor 4 (TLR4). Dysregulation or chronic stimulation of TLR4 has been implicated in multiple pathophysiological mechanisms associated with POAG and several polymorphisms in the TLR4 gene have been associated with risk of the disease. In the trabecular meshwork, TLR4 plays a role in fibrotic scarring, xidative stress, and impaired detoxification. In the optic nerve and retina, TLR4 mediates apoptotic and neuroinflammatory mechanisms of RGC death. In the vasculature, TLR4 contributes to blood-brain and blood-ocular barrier dysfunction and pro-thrombotic conditions. Here, we review the current evidence implicating TLR4 in the pathophysiology of POAG including genetic associations and mechanistic roles in the trabecular meshwork, optic nerve, and vasculature. We suggest that inhibition of TLR4 may be a viable, multimodal therapeutic strategy to target the trabecular meshwork, optic nerve/retina, and vasculature in POAG.
Glaucoma Research 2020-2022, pp. 57-72 #6
Edited by: Paul A. Knepper and John R. Samples
© Kugler Publications, Amsterdam, The Netherlands