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Published on: January 30, 2014
Microglia Activation in Retinal Ischemia Triggers Cytokine and Toll-Like Receptor Response
Natalie Wagner1, Sabrina Reinehr1, Marina Palmhof1
1Experimental Eye Research, University Eye Hospital, Ruhr-University Bochum, In der Schornau 23-25, 44892, Bochum, Germany.
Abstract:
Mechanisms and progression of ischemic injuries in the retina are still incompletely clarified. Therefore, the time course of microglia activation as well as resulting cytokine expression and downstream signaling were investigated. Ischemia was induced in one eye by transiently elevated intraocular pressure (60 min) followed by reperfusion; the other eye served as a control. Eyes were processed for RT-qPCR and immunohistochemistry analyses at 2, 6, 12, and 24 h as well as at 3 and 7 days. Already 2 h after ischemia, more microglia/macrophages were in an active state in the ischemia group. This was accompanied by an upregulation of pro-inflammatory cytokines, like IL-1β, IL-6, TNFα, and TGFβ. Activation of TLR3, TLR2, and the adaptor molecule Myd88 was also observed after 2 h. NFκB revealed a wave-like activation pattern. In addition, an extrinsic caspase pathway activation was noted at early time points, while enhanced numbers of cleaved caspase 3+ cells could be observed in ischemic retinae throughout the study. Retinal ischemia induced an early and strong microglia/macrophage response as well as cytokine and apoptotic activation processes. Moreover, in early and late ischemic damaging processes, TLR expression and downstream signaling were involved, suggesting an involvement in neuronal death in ischemic retinae. Graphical Abstract.
Insights
Retinal ischemia rapidly activates microglia and upregulates inflammatory cytokines (IL-1β, IL-6, TNFα, TGFβ) and apoptotic pathways. Toll-like receptor (TLR) signaling is involved in neuronal death during ischemic injury.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Mechanisms of retinal ischemic injury remain unclear.
- Microglia activation, cytokine expression, and downstream signaling are critical but incompletely understood aspects of retinal ischemia.
Purpose of the Study:
- To investigate the time course of microglia activation, cytokine expression, and downstream signaling pathways following retinal ischemia.
- To elucidate the role of Toll-like receptor (TLR) and caspase pathways in retinal ischemia-induced neuronal damage.
Main Methods:
- Retinal ischemia was induced by transiently elevated intraocular pressure in one eye, with the other serving as a control.
- RT-qPCR and immunohistochemistry were used to analyze eyes at multiple time points (2h to 7 days).
Main Results:
- Early microglia/macrophage activation (2h post-ischemia) was observed, accompanied by upregulation of pro-inflammatory cytokines (IL-1β, IL-6, TNFα, TGFβ).
- Activation of TLR3, TLR2, Myd88, and NFκB signaling pathways occurred early. Extrinsic caspase pathway activation and increased cleaved caspase 3+ cells were noted.
- TLR expression and downstream signaling were implicated in both early and late stages of ischemic damage and neuronal death.
Conclusions:
- Retinal ischemia triggers a rapid and robust microglia/macrophage response, cytokine release, and apoptotic processes.
- TLR signaling pathways play a significant role in the progression of neuronal death in ischemic retinae.
