Early Reduction of Microglia Activation by Irradiation in a Model of Chronic Glaucoma

Abstract

Glaucoma is a neurodegenerative disease that results in the progressive decline and ultimate death of retinal ganglion cells (RGCs). While multiple risk factors are associated with glaucoma, the mechanisms leading to onset and progression of the disease remain unknown. Molecular analysis in various glaucoma models has revealed involvement of non-neuronal cell populations, including astrocytes, Mueller glia and microglia, at early stages of glaucoma. High-dose irradiation was reported to have a significant long-term protective effect in the DBA/2J (D2) mouse model of glaucoma, although the cellular and molecular basis for this effect remains unclear. In particular, the acute effects of irradiation on specific cell populations, including non-neuronal cells, in the D2 retina and nerve have not been assessed. Here we report that irradiation induces transient reduction in proliferating microglia within the optic nerve head and glial lamina within the first week post-irradiation. This was accompanied by reduced microglial activation, with no effect on astrocyte gliosis in those regions. At later stages we confirm that early high-dose irradiation of the mouse head results in improvement of axonal structural integrity and anterograde transport function, without reduction of intraocular pressure. Thus reduced microglial activation induced by irradiation at early stages is associated with reduced optic nerve and retinal neurodegeneration in the D2 mouse model of glaucoma.

Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

“…Our previous results, 22 and those of others, 8,13,[32][33][34] have clearly established that axonal injury subsequent to chronically elevated IOP is associated with a spatially and temporally coordinated reactive microgliosis, the extent of which reflects the severity of injury. The microglial response is characterized by proliferation, expression of markers indicative of phagocytosis, and induction of immunologic cell surface markers, including MHC II.…”

“…Most pertinently, suppression of microglial activity, for example by administration of minocycline, has been shown to be neuroprotective to RGCs in models of experimental glaucoma. [10][11][12][13][14] Moreover, inhibition of reactive microgliosis also augments RGC survival in other injury models, such as ON transection/crush, 10,35,36 NMDA-induced excitotoxicity, 37 and ischemia-reperfusion. 38 The precise method by which minocycline protects RGCs, and, by implication, the specific mechanism(s) by which the microglia are toxic to RGCs, remain unclear, but suggested pathways of microglial toxicity include release of proinflammatory mediators and activation of the immune system.…”

“…In support of the hypothesis that reactive microglia are harmful to vulnerable RGCs is the body of evidence demonstrating that suppression of microglial activity is neuroprotective to RGCs in models of experimental glaucoma. [10][11][12][13][14] The principal route by which microglia induce an immune response is through expression of major histocompatibility complex (MHC) class II. 15 Microglial MHC II is immunohistochemically undetectable in healthy neuronal tissue, but expression is upregulated in response to neurodegenerative signals.…”

The Complex Role of Neuroinflammation in Glaucoma

“…This microglial reactivity is characterized by increased proliferation, increased phagocytic activity (revealed by an increase in the phagocytosis-related protein CD68), changes in morphology, and expression of proinflammatory molecules, such as members of the complement cascade, major histocompatibility complex class I, and major histocompatibility complex class II (Ebneter et al 2010;Howell et al 2011a;Bosco et al 2012). Although the role of microglia in glaucoma progression is not clear, it is notable that the extent of microglia activation is closely related to axonal degeneration in the ONH.…”

“…Although the role of microglia in glaucoma progression is not clear, it is notable that the extent of microglia activation is closely related to axonal degeneration in the ONH. In fact, reduction in microglial number is evident when axonal degeneration (but not high IOP) is prevented by radiation treatment of the eye or head in a mouse model of glaucoma Bosco et al 2012).…”