Abstract
BackgroundRetinal ganglion cell (RGC) soma death is a consequence of optic nerve damage, including in optic neuropathies like glaucoma. The activation of the innate immune network in the retina after nerve damage has been linked to RGC pathology. Since the eye is immune privileged, innate immune functions are the responsibility of the glia, specifically the microglia, astrocytes, and Müller cells that populate the retina. Glial activation, leading to the production of inflammatory cytokines, is a hallmark feature of retinal injury resulting from optic nerve damage and purported to elicit secondary degeneration of RGC somas.MethodsA mouse model of optic nerve crush (ONC) was used to study retinal glial activation responses. RGC apoptosis was blocked using Bax-deficient mice. Glial activation responses were monitored by quantitative PCR and immunofluorescent labeling in retinal sections of activation markers. ATP signaling pathways were interrogated using P2X receptor agonists and antagonists and Pannexin 1 (Panx1)-deficient mice with RGC-specific deletion.ResultsONC induced activation of both macroglia and microglia in the retina, and both these responses were dramatically muted if RGC death was blocked by deletion of the Bax gene. Macroglial, but not microglial, activation was modulated by purinergic receptor activation. Release of ATP after optic nerve damage was not mediated by PANX1 channels in RGCs.ConclusionsRGC death in response to ONC plays a principal stimulatory role in the retinal glial activation response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0558-y) contains supplementary material, which is available to authorized users.
Highlights
Retinal ganglion cell (RGC) soma death is a consequence of optic nerve damage, including in optic neuropathies like glaucoma
Microglial activation is attenuated in Bax−/− mice after crush The central hypothesis of secondary degeneration is that activation of the retinal neuroinflammatory response requires an initial wave of RGC somatic degeneration principally affected by axonal damage in the optic nerve
By 7 days post-injury, Aif1 expression in wildtype mice was dramatically elevated in the crushed eye over the contralateral eye, while Bax-deficient mice only showed a modest increase in Aif1 expression (Fig. 1a, P < 0.0001 for Bax−/− mice compared to wild types)
Summary
Retinal ganglion cell (RGC) soma death is a consequence of optic nerve damage, including in optic neuropathies like glaucoma. Since the eye is immune privileged, innate immune functions are the responsibility of the glia, the microglia, astrocytes, and Müller cells that populate the retina. Glial activation, leading to the production of inflammatory cytokines, is a hallmark feature of retinal injury resulting from optic nerve damage and purported to elicit secondary degeneration of RGC somas. Among the mechanisms that have been correlated with glaucomatous neurodegeneration is the activation of the retinal innate immune response [4,5,6], which has been replicated in animal models of glaucoma and following optic nerve trauma [7,8,9,10,11]. Activated glia have been shown to phagocytose cellular debris, generate cytokines, and present antigens [29,30,31,32,33,34]
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