Susceptibility to glaucoma damage related to age and connective tissue mutations in mice

Steinhart, Matthew R.; Cone-Kimball, Elizabeth; Nguyen, Cathy; Nguyen, Thao D.; Pease, Mary Ellen; Chakravarti, Shukti; Oglesby, Ericka; Quigley, Harry A.

doi:10.1016/j.exer.2013.12.008

Cited by 31 publications

(25 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, certain conditions, such as advancing age, can make ganglion cells more susceptible to death when exposed to the same pressure rise in some models (Kim et al, 2004; Steinhart et al, 2014). Understanding the endogenous mechanisms that minimize the pathological effects of increased mechanical strain on the neurons is a key target in preventing their loss in disease.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Lim

Beckel

et al. 2016

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Mechanical strain due to increased pressure or swelling activates inflammatory responses in many neural systems. As cytokines and chemokine messengers lead to both pro-inflammatory and neuroprotective actions, understanding the signaling patterns triggered by mechanical stress may help improve overall outcomes. While cytokine signaling in neural systems is often associated with glial cells like astrocytes and microglia, the contribution of neurons themselves to the cytokine response is underappreciated and has bearing on any balanced response. Mechanical stretch of isolated neurons was previously shown to trigger ATP release through pannexin hemichannels and autostimulation of P2X7 receptors (P2X7Rs) on the neural membrane. Given that P2X7Rs are linked to cytokine activation in other cells, this study investigates the link between neuronal stretch and cytokine release through a P2X7-dependent pathway. Cytokine assays showed application of a 4% strain to isolated rat retinal ganglion cells (RGCs) released multiple cytokines. The P2X7R agonist BzATP also released multiple cytokines; Interleukin 3 (IL-3), TNF-α, CXCL9, VEGF, L-selectin, IL-4, GM-CSF, IL-10, IL-1Rα, MIP and CCL20 were released by both stimuli, with the release of IL-3 greatest with either stimuli. Stretch-dependent IL-3 release was confirmed with ELISA and blocked by P2X7R antagonists A438079 and Brilliant Blue G (BBG), implicating autostimulation of the P2X7R in stretch-dependent IL-3 release. Neuronal IL-3 release triggered by BzATP required extracellular calcium. The IL-3Rα receptor was expressed on RGCs but not astrocytes, and both IL-3Rα and IL-3 itself were predominantly expressed in the retinal ganglion cell layer of adult retinal sections, implying autostimulation of receptors by released IL-3. While the number of surviving ganglion cells decreased with time in culture, the addition of IL-3 protected against this loss of neurons. Expression of mRNA for IL-3 and IL-3Rα increased in rat retinas stretched with moderate intraocular pressure (IOP) elevation; BBG blocked the rise in IL-3, implicating a role for the P2X7R in transcriptional regulation in vivo. In summary, mechanical stretch triggers release of cytokines from neurons that can convey neuroprotection. The enhancement of these signals in vivo implicates P2X7R-mediated IL-3 signaling as an endogenous pathway that could minimize damage following neuronal exposure to chronic mechanical strain.

show abstract

Section: Discussionmentioning

confidence: 99%

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Lim

Beckel

et al. 2016

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…IOP spikes should therefore be higher in the elderly, and even higher in persons of African descent, which may contribute to the increased glaucoma prevalence in these at risk populations. Recent work in an experimental mouse model of glaucoma supports this view, in that a stiffer sclera was associated with increased ganglion cell loss (Nguyen, Cone et al 2013, Pease, Oglesby et al 2014, Steinhart, Cone-Kimball et al 2014). Also, Vande Geest and coworkers observed that the local orientation of the collagen fibrils changes through the thickness of the sclera and was found to be different between donors of African heritage versus European heritage, although no significant changes were seen with age (Yan, McPheeters et al 2011).…”

Section: Remodeling Of the Optic Nerve Head With Age And Diseasementioning

confidence: 92%

Optic nerve head biomechanics in aging and disease

Downs

2015

Experimental Eye Research

122

View full text Add to dashboard Cite

This nontechnical review is focused upon educating the reader on optic nerve head biomechanics in both aging and disease along two main themes: what is known about how mechanical forces and the resulting deformations are distributed in the posterior pole and ONH (biomechanics) and what is known about how the living system responds to those deformations (mechanobiology). We focus on how ONH responds to IOP elevations as a structural system, insofar as the acute mechanical response of the lamina cribrosa is confounded with the responses of the peripapillary sclera, prelaminar neural tissues, and retrolaminar optic nerve. We discuss the biomechanical basis for IOP-driven changes in connective tissues, blood flow, and cellular responses. We use glaucoma as the primary framework to present the important aspects of ONH biomechanics in aging and disease, as ONH biomechanics, aging, and the posterior pole extracellular matrix (ECM) are thought to be centrally involved in glaucoma susceptibility, onset and progression.

show abstract

“…We have recently found that older CD1 mice are more susceptible to experimental glaucoma damage than younger CD1 mice. 42 Older CD1 mice have also longer eyes, which might logically lead to increased strain in the sclera, all other factors being equal. Yet, lower scleral permeability was associated here with those mouse strains less susceptible to glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Pease

Oglesby

Cone-Kimball

et al. 2014

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

PURPOSE. To determine differences in scleral permeability, as measured by diffusion of macromolecules, by using fluorescence recovery after photobleaching (FRAP), with reference to differences by mouse strain, scleral region, and the effect of experimental glaucoma.METHODS. In three mouse strains (B6, CD1, and B6 mice with mutation in collagen 8a2[Aca23]), we used FRAP to measure the diffusion of fluorescein isothiocyanate-dextran, molecular weight 40 kDa, into a photobleached zone of sclera. Scleral regions near the optic nerve head (peripapillary) and two successively more anterior regions were compared. Sclera from mouse eyes subjected to chronically elevated intraocular pressure after bead injection into the anterior chamber were compared to fellow eye controls. FRAP data were compared against estimated retinal ganglion cell axon loss in glaucomatous eyes.RESULTS. Diffusion rates of dextran molecules in the sclera were significantly greater in Aca23 and B6 mice than in CD1 mice in a multivariate model adjusted for region and axial length (P < 0.0001). Dextran diffusion significantly decreased in glaucomatous eyes, and the decline increased with greater axon loss (P ¼ 0.0003, multivariable model). Peripapillary scleral permeability was higher in CD1 than B6 and Aca23 mice (P < 0.05, multivariable model, adjusted by Bonferroni). CONCLUSIONS.Measurement of the diffusion rates of dextran molecules in the sclera showed that glaucoma leads to decreased scleral permeability in all three mouse strains tested. Among mouse strains tested, those that were more susceptible to glaucomatous loss of retinal ganglion cells had a lower scleral permeability at baseline.Keywords: glaucoma, mouse, experimental model, sclera, diffusion, permeability, photobleaching, dextran G laucoma is the second leading cause of world blindness and its principal risk factors include the effect of intraocular pressure (IOP) acting to decrease the number of retinal ganglion cells (RGCs). Intraocular pressure is a mechanical load that generates stress and strain in the sclera, which are magnified at the optic nerve head (ONH). The largest mechanical strains have been measured in in vitro inflation experiments in the peripapillary region, immediately adjacent to the ONH.1 The sclera acts on the ONH, where axons of RGCs pass out of the eye, and suffers damage related to the effects of IOP.2,3 Thus, the behavior of the sclera is highly relevant to glaucoma injury and its study may be useful in improved diagnosis as well as new therapeutic avenues.The sclera comprises three-quarters of the human ocular circumference and is 75% to 90% collagen, with additional elastin fibrils and proteoglycans. 4,5 The scleral proteoglycans include heparin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan, aggrecan, and several small leucinerich proteoglycans.6,7 These may have important functional significance for the mechanical responses of the sclera. 8 Scleral thickness is greatest at the peripapillary zone, followed by the limbus, and is...

show abstract

Susceptibility to glaucoma damage related to age and connective tissue mutations in mice

Cited by 31 publications

References 37 publications

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective

Optic nerve head biomechanics in aging and disease

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Contact Info

Product

Resources

About