Microglial control of neuronal death and synaptic properties

Bessis, Alain; Béchade, Catherine; Bernard, Delphine; Roumier, Anne

doi:10.1002/glia.20459

Cited by 403 publications

(280 citation statements)

References 84 publications

(94 reference statements)

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“…However, in the past decade neuroimmune crosstalk-direct interplay between neuronal and immune cells-has been shown to be critical for neurodevelopment (54), synaptic homeostasis (55), and adultstage neurogenesis (56) and may play beneficial roles during neurodegenerative disease (24,28). For instance, acute activation of microglia may function to protect neurons from accumulations of cytotoxic derivatives of dying cells and stress-related signaling pathways during the early stages of neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

White¹,

Sengupta²,

Saxena³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

152

218

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Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration-i.e., selective cell-loss paradigms akin to degenerative disease-are less well defined. To investigate possible roles innate immune cells play during retinal cell regeneration, we used intravital microscopy to visualize neutrophil, macrophage, and retinal microglia responses to induced rod photoreceptor apoptosis. Neutrophils displayed no reactivity to rod cell loss. Peripheral macrophage cells responded to rod cell loss, as evidenced by morphological transitions and increased migration, but did not enter the retina. Retinal microglia displayed multiple hallmarks of immune cell activation: increased migration, translocation to the photoreceptor cell layer, proliferation, and phagocytosis of dying cells. To test function during rod cell regeneration, we coablated microglia and rod cells or applied immune suppression and quantified the kinetics of (i) rod cell clearance, (ii) MG/progenitor cell proliferation, and (iii) rod cell replacement. Coablation and immune suppressants applied before cell loss caused delays in MG/progenitor proliferation rates and slowed the rate of rod cell replacement. Conversely, immune suppressants applied after cell loss had been initiated led to accelerated photoreceptor regeneration kinetics, possibly by promoting rapid resolution of an acute immune response. Our findings suggest that microglia control MG responsiveness to photoreceptor loss and support the development of immune-targeted therapeutic strategies for reversing cell loss associated with degenerative retinal conditions. retina | microglia | glucocorticoid | regeneration | macrophage N eurodegenerative diseases are caused by the loss of discrete neuronal cell types. The goal of regenerative medicine is to reverse this process. One strategy for doing so involves harnessing the regenerative potential of endogenous neural stem cells. Unfortunately, although adult neural stem cells exist in the mammalian CNS, innate potentials for neuronal repair remain dormant in the absence of exogenous stimulation. Conversely, many other species are endowed with remarkable capacities for neuronal regeneration. For instance, in the zebrafish eye, retinal Müller glia (MG) cells can dedifferentiate to a stem cell-like state and give rise to progenitors that replace lost neurons and restore visual function (1, 2). Intriguingly, human MG cells are able to give rise to new neurons in culture (3) that can restore visual function when transplanted into mammalian disease models (4), suggesting that human MG retain a stem cell-like capacity for mediating retinal repair. Mechanisms controlling the regenerative potential of MG are therefore of great interest. We and others study zebrafish to learn more about how retinal regeneration is cont...

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Section: Discussionmentioning

confidence: 99%

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

White¹,

Sengupta²,

Saxena³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

152

218

View full text Add to dashboard Cite

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“…Microglial cells represent a potential key player in the brain-immune dialogue since they mediate the influence of the inflammatory milieu on neuronal activity and, thus, on behavioral outcome (Bessis et al, 2007;Branchi et al, 2014). To evaluate whether microglial function is affected by changes in inflammatory markers induced by fluoxetine treatment in the two environmental conditions, we first measured the expression of Toll-like receptors (TLRs).…”

Section: Microglial Modulation By Fluoxetine Upon Environmental Stimumentioning

confidence: 99%

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

Alboni

Poggini

Garofalo

et al. 2016

Brain, Behavior, and Immunity

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It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti-or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti-and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions. AbstractIt has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these drugs act either as anti-or proinflammatory. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21 days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti-and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that...

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“…94 Macrophages contribute to neurogenesis, synaptogenesis and apoptosis involved in brain development. 34,95,96 They are also involved in remodelling arborisations of neurosecretory neurons 97 and contribute to synaptic pruning. 98 Another developmental function of macrophages has been observed during brain angiogenesis.…”

Section: Macrophages In Organogenesismentioning

confidence: 99%