Microglia Activation in Retinal Ischemia Triggers Cytokine and Toll-Like Receptor Response
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Microglia Activation in Retinal Ischemia Triggers Cytokine and Toll-Like Receptor Response Natalie Wagner 1 & Sabrina Reinehr 1 & Marina Palmhof 1 & David Schuschel 1 & Teresa Tsai 1 & Emely Sommer 1 & Viktoria Frank 1 & Gesa Stute 1 & H. Burkhard Dick 1 & Stephanie C. Joachim 1 Received: 19 April 2020 / Accepted: 24 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Ischemia . Microglia . Cytokine . Toll-like-receptor . NFκB . MyD88 . Caspase . IL-1β
Introduction Ischemia is based on limited blood supply in a localized area, due to the blockage of blood vessels in the affected area. This in turn causes energy exhaustion and ultimately cell death. In the retina, ischemia develops as a result of capillary blockage, results in non-perfusion of this region, and leads to dysfunction as well as death of neuronal cells (Osborne et al. 2004). This is accompanied by glia cell activation followed by a secretion of cytotoxic mediators, including cytokines. Ischemic processes occur in several eye diseases, such as diabetic retinopathy or glaucoma (Schmidl et al. 2011; Sim et al. 2013; Terelak-Borys et al. 2012).
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12031-020-01674-w) contains supplementary material, which is available to authorized users. * Stephanie C. Joachim [email protected] 1
Experimental Eye Research, University Eye Hospital, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany
Glaucoma is the second most common cause of blindness worldwide, with a rising trend due to an aging society (EGS 2014; Quigley and Broman 2006). Furthermore, glaucoma not only leads to health problems but
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