Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma

Howell, Gareth R.; Soto, Ileana; Zhu, Xianjun; Ryan, Margaret M.; Macalinao, Danilo G.; Sousa, Gregory L.; Caddle, Lura Brianna; MacNicoll, Katharine H.; Barbay, Jessica M.; Porciatti, Vittorio; Anderson, Michael G.; Smith, Richard; Clark, Abbot F.; Libby, Richard T.; John, Simon W. M.

doi:10.1172/jci61135

Cited by 202 publications

(313 citation statements)

References 90 publications

(116 reference statements)

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“…The method of preparing, staining, and analyzing optic nerves for damage has been previously described and validated (5,8,20,27,34,39). In brief, cross-sections of optic nerve are stained with paraphenylenediamine (PPD), which stains all myelin sheaths but darkly stains the axoplasm of injured or dying axons.…”

Section: Methodsmentioning

confidence: 99%

“…Nerves with no or early (NOE) glaucoma have healthy axons (i.e., intact myelin sheaths and clear axoplasm). They have no morphologically detectable glaucomatous damage, but some are at early molecular stages of glaucoma (5,8). Moderately (MOD) affected nerves have readily detectable degenerating axons, as marked by darkly stained axoplasm; however, the majority of axons are still healthy.…”

Section: Methodsmentioning

confidence: 99%

“…Splenocytes were labeled using 6-carboxyfluorescein diacetate (6-CFDA; Invitrogen) via intrasplenic injection, as described previously (5). At 72 h postinjection, mice were euthanized, eyes were harvested, and retinas and ONHs were dissected and fixed in 4% PFA and flat-mounted on glass slides.…”

Section: Methodsmentioning

confidence: 99%

“…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)(6)(7)(8)(9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12).…”

mentioning

confidence: 99%

“…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)(14)(15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve.…”

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confidence: 99%

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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.

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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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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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.

Self Cite

103

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An energy theory of glaucoma

Liu

Xiao

et al. 2015

Glia

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A radial array of fortified astrocytes (FASTs) is the load bearing structure of the rat optic nerve head (ONH). At the retinal end the ONH is suspended on a fluid filled extracellular space occupied by modified pigment cells which generate a glomerular-like formation of villi. We propose that regulation of fluid in and out of this space may contribute to buffering the normal fluctuations of intraocular pressure. The energy requirement for the fluid transfer process is provided by the dense vascularity of the ONH and is reflected in the giant mitochondria of the FASTs. We propose that glaucoma occurs when a maintained rise in pressure overwhelms the capacity of this regulatory system. Under these circumstances the FAST array becomes detached from its anchorage in the surrounding ONH sheath. Progressively driven backwards by the pressure, the FASTs degenerate. We propose that the degeneration of the FASTs is associated with ischemic damage caused by the backward stretching of their blood supply. Retraction of the FAST processes deprives the retinal ganglion cell axons of their energy support, resulting in axotomy. We consider that our previously observed rescue of axons and FASTs by transplantation of olfactory ensheathing cells is due to replacement of this lost energy source.

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Neuroinflammation and microglia in glaucoma: time for a paradigm shift

Wei

Cho

Thee

et al. 2018

J of Neuroscience Research

156

134

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Glaucoma is a complex neurodegenerative disease with many clinical subtypes. Some of its rare forms include pigmentary glaucoma, uveitic glaucoma and congenital glaucoma. While they all share common features of progressive retinal ganglion cell (RGC) loss, optic nerve damage and corresponding visual field loss, the exact mechanisms underlying glaucomatous neuron loss are not clear. This has largely hindered the development of a real cure for this disease. Elevated intraocular pressure (IOP) is a known major risk factor of glaucoma; however, progressive degeneration of RGCs and axons can also be found in patients with a normal IOP, i.e., normal tension glaucoma (NTG). Interestingly, patients who carry the gain-of-function mutation of the pro-inflammatory gene TBK1 - tumor necrosis factor (TNF) receptor associated factor NF-κB activator (TANK) binding kinase 1 - are at increased risk to develop NTG. This finding suggests a causal link between neuroinflammatory processes and glaucoma. Various studies have reported the presence of neuroinflammatory responses by microglia, astrocytes and other blood-born immune cells in the optic nerve head (ONH) at early stages of experimental glaucoma. Inhibition of certain pro-inflammatory pathways, particularly those associated with microglial activation, appears to be neuroprotective. In this review, we will focus on the inflammatory responses, in particular the proposed roles of microglia, in the pathogenesis of glaucoma.

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Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma

Cited by 202 publications

References 90 publications

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

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

An energy theory of glaucoma

Neuroinflammation and microglia in glaucoma: time for a paradigm shift

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