Network analysis of human glaucomatous optic nerve head astrocytes

Nikolskaya, Tatiana; Nikolsky, Yuri; Serebryiskaya, Tatiana; Zvereva, Svetlana; Sviridov, Eugene; Dezső, Zoltán; Rahkmatulin, Eugene; Brennan, Richard; Yankovsky, N. K.; Bhattacharya, Sanjoy K.; Agapova, Olga A.; Hernandez, M. Rosario; Shestopalov, Valery I.

doi:10.1186/1755-8794-2-24

Cited by 50 publications

(49 citation statements)

References 103 publications

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“…These inflammatory processes may be either damaging or protective (52,53), and future experiments are needed to determine the roles of specific molecules. It is difficult to compare our data with previous gene expression profiling studies of human glaucoma and animal models of glaucoma, as the complete datasets are not always available, and criteria for determining DE genes can vary (22,(24)(25)(26)54). Nevertheless some similarities are evident, including changes in immune/inflammatory and ECM genes.…”

Section: Figurementioning

confidence: 57%

Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma

Howell¹,

Macalinao²,

Sousa³

et al. 2011

J. Clin. Invest.

399

585

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Glaucoma is one of the most common neurodegenerative diseases. Despite this, the earliest stages of this complex disease are still unclear. This study was specifically designed to identify early stages of glaucoma in DBA/2J mice. To do this, we used genome-wide expression profiling of optic nerve head and retina and a series of computational methods. Eyes with no detectable glaucoma by conventional assays were grouped into molecularly defined stages of disease using unbiased hierarchical clustering. These stages represent a temporally ordered sequence of glaucoma states. We then determined networks and biological processes that were altered at these early stages. Early-stage expression changes included upregulation of both the complement cascade and the endothelin system, and so we tested the therapeutic value of separately inhibiting them. Mice with a mutation in complement component 1a (C1qa) were protected from glaucoma. Similarly, inhibition of the endothelin system with bosentan, an endothelin receptor antagonist, was strongly protective against glaucomatous damage. Since endothelin 2 is potently vasoconstrictive and was produced by microglia/macrophages, our data provide what we believe to be a novel link between these cell types and vascular dysfunction in glaucoma. Targeting early molecular events, such as complement and endothelin induction, may provide effective new treatments for human glaucoma.

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Section: Figurementioning

confidence: 57%

Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma

Howell¹,

Macalinao²,

Sousa³

et al. 2011

J. Clin. Invest.

399

585

View full text Add to dashboard Cite

show abstract

“…Changes in astrocyte morphology, such as enlargement of the cell body and processes, as well as up-regulation of cytoskeletal and extracellular matrix proteins, have been observed in the retina and ONH in human glaucoma (Wang et al 2002;Inman and Horner 2007;Hernandez et al 2008;Kompass et al 2008;Nikolskaya et al 2009). Several studies have demonstrated that this reactivity and remodeling of astrocytes, and the increased deposition of extracellular matrix occur in early stages of experimental glaucoma (Johnson and Morrison 2009;Howell et al 2011a;Johnson et al 2011;Lye-Barthel et al 2013;Qu and Jakobs 2013).…”

Section: Activation Of Astrocytes and Microglia In The Optic Nerve Hementioning

confidence: 99%

The Complex Role of Neuroinflammation in Glaucoma

Soto

Howell

2014

Cold Spring Harbor Perspectives in Medicine

190

156

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“…2, 15, 23). These studies identified changes in multiple genes/pathways related to immune responses, as well as structural and inflammatory changes in the ONH (8,24,25). The cause and impact of most of these changes in glaucoma remain to be determined, however.…”

mentioning

confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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Network analysis of human glaucomatous optic nerve head astrocytes

Abstract: Background: Astrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive.

Cited by 50 publications

References 103 publications

Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma

Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma

The Complex Role of Neuroinflammation in Glaucoma

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

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