Oxidative Stress and the Regulation of Complement Activation in Human Glaucoma

Tezel, Gülgün; Yang, Xiangjun; Luo, Cheng; Kain, Angela D.; Powell, David W.; Kuehn, Markus H.; Kaplan, Henry J.

doi:10.1167/iovs.10-5289

Cited by 187 publications

(185 citation statements)

References 74 publications

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“…Deposition of C1QA protein was also observed in RGC dendrites in glaucomatous DBA/2J retinas as well as in primate and human glaucomatous retinas (Fig. 5A) (Kuehn et al 2006;Stasi et al 2006;Stevens et al 2007;Tezel et al 2010 Cell infiltration was also assessed using the injection of a fluorescent tracer into the spleen (CFDA, green). Spleen-derived CFDA þ cells entered the optic nerves of untreated DBA/2J eyes but not Rad-D2 eyes or control eyes .…”

Section: The Complement Cascade In Glaucomamentioning

confidence: 97%

“…Components of the complement cascade are induced in human and animal models of glaucoma, suggesting a key role for this system in progression of the disease (Ahmed et al 2004;Kuehn et al 2006Kuehn et al , 2008Stasi et al 2006;Steele et al 2006;Stevens et al 2007;Ren and Danias 2010;Tezel et al 2010;Howell et al 2011a). In experimental models of glaucoma, induction of complement components in the retina and ONH was one of the earliest signaling responses to high IOP (Howell et al 2011a;Johnson et al 2011).…”

Section: The Complement Cascade In Glaucomamentioning

confidence: 99%

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The Complex Role of Neuroinflammation in Glaucoma

Soto

Howell

2014

Cold Spring Harbor Perspectives in Medicine

177

140

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Section: The Complement Cascade In Glaucomamentioning

confidence: 97%

Section: The Complement Cascade In Glaucomamentioning

confidence: 99%

The Complex Role of Neuroinflammation in Glaucoma

Soto

Howell

2014

Cold Spring Harbor Perspectives in Medicine

177

140

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“…The earliest opsonin significantly up-regulated in each dataset was the complement component 3 (C3; D2.Wld s , +1.9-fold; D2, +1.4-fold; D2 stage 1a, +3.9-fold; D2 stage 1b, +3.3-fold). Complement activation has been identified in human glaucoma (50,51), and components of the complement cascade are known to mediate RGC loss and optic nerve degeneration in D2 glaucoma (8,51,52). In support of an important role for C3 effector fragments (C3a and C3b) during early stages of glaucoma, expression of a C3a receptor (C3ar1), a C3b receptor (CR4 receptor consisting of an Itgax and Itgb2 dimer), and the alternative pathway component C3 convertase (Cfb) were increased in glaucoma stage 1a and all subsequent stages (Fig.…”

Section: Up-regulation Of Complement Component C3 Is An Early Immunementioning

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.

100

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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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“…Findings from numerous studies support the notion that both the innate and adaptive immune responses are involved in the pathogenesis of glaucoma. 1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Yet, the precise mechanisms of immune responses and the specific cell interactions contributing to the disease process are still not fully understood. Many questions remain about the role of the immune system in glaucoma ( Figure 1).…”

Section: The Immune System Has Been Implicated In the Pathogenesis Ofmentioning

confidence: 99%