Müller cells in the healthy and diseased retina Bringmann, Andreas; Pannicke, Thomas; Grosche, Jens ...
Progress in retinal and eye research,
07/2006, Letnik:
25, Številka:
4
Journal Article
Recenzirano
Müller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of ...functional interactions between neurons and Müller cells, including a ‘metabolic symbiosis’ and the processing of visual information. Müller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Müller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Müller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Müller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Müller cells display a dysregulation of various neuron-supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Müller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Müller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Müller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Müller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Müller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective—and prevent the destructive—mechanisms of gliosis.
Highlights • BDNF inhibits osmotic swelling of glial and bipolar cells in retinal slices. • Swelling inhibition is mediated by TrkB and FGF signaling. • BDNF inhibits the swelling of isolated glial ...but not bipolar cells. • BDNF induces glial release of factors that inhibit bipolar cell swelling. • Retinal glial cells regulate the volume of retinal neurons.
Highlights • Osteopontin inhibits osmotic swelling of retinal glial cells. • Osteopontin does not inhibit osmotic swelling of bipolar cells. • Osteopontin induces glial release of VEGF and adenosine. ...• Retinal glial cells are immunolabeled for osteopontin. • Inhibition of cytotoxic glial swelling may be neuroprotective.
Proliferative vitreoretinal retinopathy (PVR) is a very severe complication of vitreoretinal surgery. PVR is characterised by a complex cellular reaction. This corresponds to a vitreoretinal wound ...healing reaction and leads to tractional retinal detachment fixed by membranes. A rational goal of treatment is the removal of active cells and membranes, particularly the whole vitreous body; this can only be achieved surgically.
Much progress and significant therapeutic changes have been made in the field of tumor therapy in the past decades. Besides chemotherapy and radiotherapy, a special focus was laid on targeted ...therapies such as small molecule tyrosine kinase inhibitors (TKIs) and other immunomodulatory drugs, which have become standard therapies and important combination partners in a variety of malignancies. In contrast to the widely established use of these often anti-angiogenic drugs, many functional molecular mechanisms are yet not completely understood. Recent analyses focused not only on their direct anti-tumor responses, but also on their influence on tumor microenvironment, as well as on their effects on malignant and healthy cells. Different anti-angiogenic compounds targeting the vascular endothelial growth factor (VEGF) or platelet-derived growth factor pathways seem to be capable of modulating immune responses, in a positive, as well as apparently harmful manner. For an optimal clinical anti-cancer treatment, a better understanding of these immunomodulatory effects is necessary. Here we summarize recent reports on the immunomodulatory function of lately introduced clinically applied anti-angiogenic compounds, such as the humanized monoclonal antibody against VEGF bevacizumab, the small molecule TKIs sunitinib, sorafenib, imatinib, dasatinib, nilotinib and the proteasome inhibitor bortezomib.
Gliosis of retinal Müller glial cells may have both beneficial and detrimental effects on neurons. To investigate the role of purinergic signaling in ischemia-induced reactive gliosis, transient ...retinal ischemia was evoked by elevation of the intraocular pressure in wild-type (Wt) mice and in mice deficient in the glia-specific nucleotide receptor P2Y1 (P2Y1 receptor-deficient (P2Y1R-KO)). While control retinae of P2Y1R-KO mice displayed reduced cell numbers in the ganglion cell and inner nuclear layers, ischemia induced apoptotic death of cells in all retinal layers in both, Wt and P2Y1R-KO mice, but the damage especially on photoreceptors was more pronounced in retinae of P2Y1R-KO mice. In contrast, gene expression profiling and histological data suggest an increased survival of amacrine cells in the postischemic retina of P2Y1R-KO mice. Interestingly, measuring the ischemia-induced downregulation of inwardly rectifying potassium channel (Kir)-mediated K(+) currents as an indicator, reactive Müller cell gliosis was found to be weaker in P2Y1R-KO (current amplitude decreased by 18%) than in Wt mice (decrease by 68%). The inner retina harbors those neurons generating action potentials, which strongly rely on an intact ion homeostasis. This may explain why especially these cells appear to benefit from the preserved Kir4.1 expression in Müller cells, which should allow them to keep up their function in the context of spatial buffering of potassium. Especially under ischemic conditions, maintenance of this Müller cell function may dampen cytotoxic neuronal hyperexcitation and subsequent neuronal cell loss. In sum, we found that purinergic signaling modulates the gliotic activation pattern of Müller glia and lack of P2Y1 has janus-faced effects. In the end, the differential effects of a disrupted P2Y1 signaling onto neuronal survival in the ischemic retina call the putative therapeutical use of P2Y1-antagonists into question.
Abstract The volume homeostasis of retinal glial cells is mediated by an autocrine purinergic mechanism of ion channel opening which is activated in response to a decrease in the extracellular ...osmolarity. Here, we show that erythropoietin (EPO) prevents the osmotic swelling of glial somata in retinal slices and of isolated glial cells from control and diabetic rats, with a half-maximal effect at ∼0.01 nM. The downstream signaling evoked by EPO includes a release of vascular endothelial growth factor from the cells which was blocked by Janus kinase and extracellular signal-regulated kinases (ERK)1/2 inhibitors. Transactivation of kinase insert domain-containing receptor/fms-like tyrosine kinase 1 (KDR/flk-1) evokes a calcium-dependent, exocytotic release of glutamate, followed by activation of group I/II metabotropic glutamate receptors which results in calcium-independent release of ATP and adenosine from the cells. The final step in this cascade is the activation of adenosine A1 receptors which results in protein kinase A- and phosphoinositide 3-kinase-mediated opening of potassium and chloride channels. EPO receptor protein was immunohistochemically localized to the inner retina and photoreceptor inner segments. In isolated glial cells, EPO receptor protein is selectively localized to fibers which traverse the inner nuclear layer in situ . Inhibition of glial swelling might contribute to the neuroprotective action of EPO in the retina under pathological conditions.
Abstract Gliotransmitters such as glutamate and ATP play an essential role in the prevention of the osmotic swelling of retinal glial (Müller) cells. It has been shown that vascular endothelial ...growth factor (VEGF) induces a Ca2+ -dependent release of glutamate from the cells Wurm et al. (2008), J Neurochem 104:386–399. In the present study, we investigated with cell swelling experiments on freshly isolated retinal glial cells of the rat whether activation of voltage-gated Na+ (Nav ) and Ca2+ channels (VGCCs) is implicated in mediating the VEGF-induced release of glutamate. We found that the inhibitory effect of VEGF on the osmotic swelling of retinal glial cells, used as an indicator of glutamate release, is prevented in the presence of selective blockers of T-type VGCCs (kurtoxin, mibefradil, Ni2+ ) and Nav channels (TTX, saxitoxin, phenytoin). In contrast, the swelling-inhibitory effect of glutamate, that is mediated by a downstream release of ATP, remained unaffected in the presence of the blockers. The cells displayed immunolabeling for VGLUT3, Cav 1.2, Cav 3.1, and Nav 1.6. In addition to VEGF, various other receptor agonists including neuropeptide Y, progesterone, erythropoietin, and endothelin-1 evoked a VGCC- and Nav channel-dependent release of glutamate. It is concluded that activation of T-type VGCCs and Nav channels is implicated in mediating the ligand-induced release of glutamate from retinal glial cells of the rat. The involvement of VLGUTs might suggest that glutamate is released by vesicular exocytosis.
Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In ...this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3beta were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-kappaB transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.
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