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.

Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels

“…Our findings include (i) identification of the NPE osmosensor as TRPV4, (ii) discovery that calcium ions potentiate NPE swelling, (iii) observation of differential osmoregulation and Ca 2+ homeostasis mechanisms in NPE vs. PE cells, and (iv) previously unidentified role for lipid metabolism in calcium signaling and osmoregulation within the CB. By showing differential contributions to volume regulation and Ca 2+ signaling in a tightly coupled epithelial syncytium that plays an essential function in mammalian vision, these findings expand the known key role for TRPV4 in epithelial gene expression, intracellular signaling, protein transport, and secretion (11, 13-15, 30, 37, 38) and place it within the context of ocular volume regulation (39).…”

“…It is therefore noteworthy that NPE and PE layers differ in volume sensing, regulation, and the expression and function of volumeactivated Cl − channels, K + channels, PMCAs, Na/K ATPases, and NKCC transporters (5,33,43,44). The distinctiveness of volume regulatory and Ca 2+ homeostatic apparati is consistent with the strikingly different functions in generation and secretion of aqueous humor (2,4 -dependent activity of Na/K ATPases, the primary determinant of aqueous humor secretion (2,5,32,39). Consistent with this conjecture, topical application of Ca 2+ ionophores elevates IOP without significantly changing the outflow facility (50).…”

Rat, Mouse, and Primate Models of Chronic Glaucoma Show Sustained Elevation of Extracellular ATP and Altered Purinergic Signaling in the Posterior Eye

“…1,2 While abnormally high IOP is a widely recognized risk factor, 3,4 the molecular pathways linking elevated IOP and RGC loss are complex. Although several inroads toward understanding the mechanisms have recently been made, [5][6][7][8][9][10][11][12][13] much remains to be learned, particularly regarding the responses in chronic injury. Extracellular ATP is a likely candidate to link the elevated IOP in glaucoma to perturbed signaling in the retina and optic nerve.…”

A Treatise of the Physical Aspects of Phosphenes and Single-Cell Selectivity in Retinal Stimulation

“…Experimental data of microelectrodes coated with PEDOT-NaPSS was used in our model. PEDOT-NaPSS was applied by electrode position with a charge density of 40 mC/cm 2 . This results in a thin thickness of 200 nm [32].…”

“…A phosphene is defined as any visual sensation represented as a spot of light in the visual field caused by methods other than stimulation of the visual system by light. Phosphenes can be elicited by mechanical forces [2], magnetic stimulation [3][4][5] or electrical stimulation [6][7][8][9][10][11][12][13][14][15].…”