Microglia Activation in Retinal Ischemia Triggers Cytokine and Toll-Like Receptor Response

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 Electronic supplementary material The online version of this article (10.1007/s12031-020-01674-w) contains supplementary material, which is available to authorized users.

Glia-Mediated Antigen Presentation In The Retina During Degeneration

“…In the retina, their interplay is well-characterized only in animal models of autoimmune uveitis (Lipski et al, 2017; Okunuki et al, 2019) and little is known in retinal degenerative diseases. However, we know that CD4 + T-cells are recruited to the parenchyma in mice with experimental ischemic retinopathy and laser-injuries and both models also involved glial activation (Conedera et al, 2023; Khanh Vu et al, 2020; Wagner et al, 2021). Interestingly, other recent publications implied the connection between resident immune cells and CD4 + T-cells showing that the depletion of CD4 + T-cells leads to the accumulation of pro-inflammatory microglia (Llorián-Salvador et al, 2024).…”

Synthesis, Characterization, and in vivo Evaluation of a Novel Potent Autotaxin-Inhibitor

“…Ischemia injury has been shown to involve activation of microglia cells ( Zhang et al, 2005 ; Cho et al, 2011 ; Schmid et al, 2014 ; Wagner et al, 2020 ), which play an important role as phagocytic cells to remove cell debris ( Xu et al, 2016 ). In line with this, the total number as well as the number of activated microglia was elevated after I/R at both points in time.…”

“…At both points in time, more apoptotic cells in the GCL were noted in I/R and I/R + ATX-i retinas (Figures 7D,E). Previously, more cleaved caspase 3 + cells were observed already 2 h after I/R induction (Wagner et al, 2020). The severe damage following the ischemia induction could explain the lack of treatment effects on apoptotic cell numbers.…”

“…Less RGCs could be detected on protein level already 2 h after I/R and on mRNA level at 12 h ( Palmhof et al, 2019 ). In addition, 2 h after I/R induction, microglia/macrophages are already in an active state ( Wagner et al, 2020 ).…”

Role of myeloid cells in ischemic retinopathies: recent advances and unanswered questions

“…Myeloid cells respond to retinal ischemia by secreting cytokines. According to a recent study, microglia activation after retinal ischemia triggers a cytokine and Toll-like receptor response in the IR murine model by two hours after ischemia [ 99 ]. During the acute phase of injury, activated microglia release pro-inflammatory mediators, including tumor necrosis alpha (TNF-α) and interleukin 1 beta (IL-1β), through activation of the inflammasome which can contribute to tissue damage [ 100 – 102 ].…”