From Mechanosensitivity to Inflammatory Responses: New Players in the Pathology of Glaucoma

Abstract

Purpose of the study: Many blinding diseases of the inner retina are associated with degeneration and loss of retinal ganglion cells (RGCs). Recent evidence implicates several new signaling mechanisms as causal agents associated with RGC injury and remodeling of the optic nerve head. Ion channels such as Transient receptor potential vanilloid isoform 4 (TRPV4), pannexin-1 (Panx1) and P2X7 receptor are localized to RGCs and act as potential sensors and effectors of mechanical strain, ischemia and inflammatory responses. Under normal conditions, TRPV4 may function as an osmosensor and a polymodal molecular integrator of diverse mechanical and chemical stimuli, whereas P2X7R and Panx1 respond to stretch- and/or swelling-induced adenosine triphosphate release from neurons and glia. Ca²⁺ influx, induced by stimulation of mechanosensitive ion channels in glaucoma, is proposed to influence dendritic and axonal remodeling that may lead to RGC death while (at least initially) sparing other classes of retinal neuron. The secondary phase of the retinal glaucoma response is associated with microglial activation and an inflammatory response involving Toll-like receptors (TLRs), cluster of differentiation 3 (CD3) immune recognition molecules associated with the T-cell antigen receptor, complement molecules and cell type-specific release of neuroactive cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The retinal response to mechanical stress thus involves a diversity of signaling pathways that sense and transduce mechanical strain and orchestrate both protective and destructive secondary responses.

Conclusions: Mechanistic understanding of the interaction between pressure-dependent and independent pathways is only beginning to emerge. This review focuses on the molecular basis of mechanical strain transduction as a primary mechanism that can damage RGCs. The damage occurs through Ca²⁺-dependent cellular remodeling and is associated with parallel activation of secondary ischemic and inflammatory signaling pathways. Molecules that mediate these mechanosensory and immune responses represent plausible targets for protecting ganglion cells in glaucoma, optic neuritis and retinal ischemia.

• ATP
• calcium
• cytokines
• glaucoma
• glia
• inflammation
• mechanosensation
• retinal ganglion cells

Acknowledgements

Supported by NIH grants T32DC008553 (DAR), EY14232, EY021517 (VIS), EY013434, EY015537 (CHM), EY13870, EY022076 (DK), EY018666 and GM060019 (VZS), EY013813 and EY017131 (GT), Center Grants P30 EY014801 (VIS) and P30 EY14800 (DK), Department of Defense (VIS, DK), Russian Federal Special Program Grant 2012-1.5-12-000-1002-018 (V.I.S.), University of Utah Translational Seed grant (DK), State of Utah TCIP (DK), Foundation Fighting Blindness (DK) and unrestricted grants from RPB to Bascom Palmer Eye Institute (Miami) and Moran Eye Institute (Salt Lake City). The authors would like to thank Dr. Harilaos Ginis (University of Crete, Greece) for helpful comments.