Articles

The innate immune system in primary openangle glaucoma

Author(s):

Paul Knepper

Nicholas M. Pfahler

Kevin Carey

Indre Bielskus


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Abstract:

Purpose: Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide and is characterized
by cupping of the optic nerve head and degeneration of retinal ganglion cells leading to visual field loss. The vascular theory of POAG suggests that vascular abnormalities leading to ischemia of the optic nerve head result in characteristic glaucomatous injury. Recent studies from our laboratory support the vascular theory, indicating that POAG is associated with an increased prevalence of systemic microvascular abnormalities and cerebrovascular disease. These prothrombotic changes are mediated by innate immune receptor Toll-like receptor 4 (TLR4) and exacerbated by beta-amyloid, the hallmark protein of Alzheimer’s disease (AD).
Methods: TLR4 was examined as a possible therapeutic target for the treatment of POAG and AD and inhibitors were examined for three legs of the TLR4 pathway: the TLR4 receptor (naltrexone), the down-stream MyD88-dependent pathway (quercetin), and the down-stream MyD88-independent pathway (resveratrol). While systemic causal factors in POAG have remained elusive, our studies of TLR4 provide insight into improving management of the disease and could lead to a systemic treatment for POAG and AD.
Results: TLR4 expression is increased in POAG patients, as are several tissue-injury related agonists known as damage-associated molecular patterns (DAMPs). We identified 30 putative DAMP agonists located in the nucleus (n = 4), extracellular matrix (n = 15), cytosol (n = 7), and plasma membrane (n = 5). Low micromolar concentrations of TLR4 inhibitors significantly decreased superactivated platelets (SAPs) in POAG platelets (a
44% decrease) and in AD platelets (a 33.4% decrease). Notably, the innate immune system is intricately linked
to coagulation through TLR4 and the complement system, suggesting that chronic immune activation is associated with increased thrombosis. These findings may shed light on the increased presence of ischemic microvascular injury in POAG and AD.—
Conclusion: Among the major innate immune receptors, TLR4 plays a significant role in inflammatory and
apoptotic processes associated with POAG. Chronic activation of TLR4 and the complement system may lead to glaucomatous injury, suggesting that these pathways may be viable therapeutic targets in POAG. Inhibitors of TLR4 ― reseveratrol, quercetin, and naltrexone (RQN) ― block all three legs of the TLR4 signaling pathway and acts synergistically to reduce SAP levels in vitro. Notably, the synergistic dose of the three-drug combination is easily obtainable by oral administration. The in-vitro effects of RQN on SAPs may allow for optimum drug dose intervention in clinical trials based on pre-clinical testing. While further trials are required to determine in-vivo drug effects, our initial results provide a new look at reducing procoagulant platelet activity in POAG and AD.

Glaucoma Research 2018-2020, pp. 17-33 #2
Edited by: John R. Samples and Paul A. Knepper
© Kugler Publications, Amsterdam, The Netherlands


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