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

David Križaj, Daniel A. Ryskamp, Ning Tian, Gülgün Tezel, Claire H. Mitchell, Vladlen Z Slepak, Valery I Shestopalov

Research output: Contribution to journalArticle

72 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)105-119
Number of pages15
JournalCurrent Eye Research
Volume39
Issue number2
DOIs
StatePublished - Feb 1 2014

Fingerprint

Retinal Ganglion Cells
Glaucoma
Pathology
TRPV Cation Channels
Ion Channels
Protein Isoforms
Ischemia
Purinergic P2X7 Receptors
Retinal Neurons
Optic Neuritis
Mechanical Stress
Neuronal Plasticity
Toll-Like Receptors
Optic Disk
T-Cell Antigen Receptor
Interleukin-1
Neuroglia
Ganglia
Retina
Cell Death

Keywords

  • ATP
  • Calcium
  • Cytokines
  • Glaucoma
  • Glia
  • Inflammation
  • Mechanosensation
  • Retinal ganglion cells

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

From Mechanosensitivity to Inflammatory Responses : New Players in the Pathology of Glaucoma. / Križaj, David; Ryskamp, Daniel A.; Tian, Ning; Tezel, Gülgün; Mitchell, Claire H.; Slepak, Vladlen Z; Shestopalov, Valery I.

In: Current Eye Research, Vol. 39, No. 2, 01.02.2014, p. 105-119.

Research output: Contribution to journalArticle

Križaj, David ; Ryskamp, Daniel A. ; Tian, Ning ; Tezel, Gülgün ; Mitchell, Claire H. ; Slepak, Vladlen Z ; Shestopalov, Valery I. / From Mechanosensitivity to Inflammatory Responses : New Players in the Pathology of Glaucoma. In: Current Eye Research. 2014 ; Vol. 39, No. 2. pp. 105-119.
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