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Andy J Fische - One of the best experts on this subject based on the ideXlab platform.
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reactive Microglia and il1β il 1r1 signaling mediate neuroprotection in excitotoxin damaged mouse retina
Journal of Neuroinflammation, 2019Co-Authors: Levi Todd, Ning Qua, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh Hoang, Warre A Campbell, Seth Lackshaw, Andy J FischeAbstract:Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including Microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage. Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell death was assessed in wild type, IL-1R1 null mice, and mice expressing IL-1R1 only in astrocytes. NMDA-induced damage included neuronal cell death, Microglial reactivity, upregulation of pro-inflammatory cytokines, and genes associated with IL1β-signaling in different types of retinal neurons and glia. Expression of the IL1β receptor, IL-1R1, was evident in astrocytes, endothelial cells, some Muller glia, and OFF bipolar cells. Ablation of Microglia with clodronate liposomes or Csf1r antagonist (PLX5622) resulted in elevated cell death and diminished neuronal survival in excitotoxin-damaged retinas. Exogenous IL1β stimulated the proliferation and reactivity of Microglia in the absence of damage, reduced numbers of dying cells in damaged retinas, and increased neuronal survival following an insult. IL1β failed to provide neuroprotection in the IL-1R1-null retina, but IL1β-mediated neuroprotection was rescued when expression of IL-1R1 was restored in astrocytes. We conclude that reactive Microglia provide protection to retinal neurons, since the absence of Microglia is detrimental to survival. We propose that, at least in part, the survival-influencing effects of Microglia may be mediated by IL1β, IL-1R1, and interactions of Microglia and other macroglia.
Sylvain Chemtob - One of the best experts on this subject based on the ideXlab platform.
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Chemtob S: Potential role of Microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 2006
2020Co-Authors: Daniella Checchin, Florian Sennlaub, Etienne Levavasseur, Martin Leduc, Sylvain ChemtobAbstract:PURPOSE. The role of Microglia, present in the retina early in development before vascularization, remains ill defined. The authors investigated whether Microglia are implicated in retinal blood vessel formation. METHODS. The Microglia and vasculature of developing human fetal and rodent retinas were examined by labeling the endothelial cells with lectin and the Microglia with CD18 antibody or green fluorescent protein driven by the promoter of the chemokine receptor CX 3 CR1. Rodent ischemic proliferative retinopathy induced by hyperoxia or hypercapnia, which model retinopathy of prematurity, and ex vivo retinal explants were used to assess Microglial involvement in vascular pathology. Microglial participation in developmental retinal vessel formation was further studied in neonatal rats after pharmacologic macrophage depletion with the use of clodronate liposomes and subsequent intravitreal injection of Microglia. RESULTS. Microglia intimately appose developing vessels of human and murine retinas. Ischemic retinopathy models exhibit decreased Microglia concomitant with the characteristic reductions in vasculature observed in these retinopathies. Retinal explants exposed to conditions resulting in ischemic retinopathies (in vivo) reveal that antioxidants protect against Microglial loss. Depletion of resident retinal Microglia, but not systemic macrophages, reduced developmental vessel growth and density, which were restored by intravitreal Microglial injection. CONCLUSIONS. These observations suggest that proper retinal blood vessel formation requires an adequate resident Microglial population because diminished Microglia are associated with decreased vascularity in models of ischemic retinopathy and retinal vascular development. In light of these findings, the traditional definition of Microglia as merely immunocompetent cells should be reconsidered to encompass this new function related to blood vessel formation. (Invest Ophthalmol Vis Sci
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potential role of Microglia in retinal blood vessel formation
Investigative Ophthalmology & Visual Science, 2006Co-Authors: Daniella Checchin, Florian Sennlaub, Etienne Levavasseur, Martin Leduc, Sylvain ChemtobAbstract:Purpose The role of Microglia, present in the retina early in development before vascularization, remains ill defined. The authors investigated whether Microglia are implicated in retinal blood vessel formation. Methods The Microglia and vasculature of developing human fetal and rodent retinas were examined by labeling the endothelial cells with lectin and the Microglia with CD18 antibody or green fluorescent protein driven by the promoter of the chemokine receptor CX(3)CR1. Rodent ischemic proliferative retinopathy induced by hyperoxia or hypercapnia, which model retinopathy of prematurity, and ex vivo retinal explants were used to assess Microglial involvement in vascular pathology. Microglial participation in developmental retinal vessel formation was further studied in neonatal rats after pharmacologic macrophage depletion with the use of clodronate liposomes and subsequent intravitreal injection of Microglia. Results Microglia intimately appose developing vessels of human and murine retinas. Ischemic retinopathy models exhibit decreased Microglia concomitant with the characteristic reductions in vasculature observed in these retinopathies. Retinal explants exposed to conditions resulting in ischemic retinopathies (in vivo) reveal that antioxidants protect against Microglial loss. Depletion of resident retinal Microglia, but not systemic macrophages, reduced developmental vessel growth and density, which were restored by intravitreal Microglial injection. Conclusions These observations suggest that proper retinal blood vessel formation requires an adequate resident Microglial population because diminished Microglia are associated with decreased vascularity in models of ischemic retinopathy and retinal vascular development. In light of these findings, the traditional definition of Microglia as merely immunocompetent cells should be reconsidered to encompass this new function related to blood vessel formation.
Levi Todd - One of the best experts on this subject based on the ideXlab platform.
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reactive Microglia and il1β il 1r1 signaling mediate neuroprotection in excitotoxin damaged mouse retina
Journal of Neuroinflammation, 2019Co-Authors: Levi Todd, Ning Qua, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh Hoang, Warre A Campbell, Seth Lackshaw, Andy J FischeAbstract:Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including Microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage. Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell death was assessed in wild type, IL-1R1 null mice, and mice expressing IL-1R1 only in astrocytes. NMDA-induced damage included neuronal cell death, Microglial reactivity, upregulation of pro-inflammatory cytokines, and genes associated with IL1β-signaling in different types of retinal neurons and glia. Expression of the IL1β receptor, IL-1R1, was evident in astrocytes, endothelial cells, some Muller glia, and OFF bipolar cells. Ablation of Microglia with clodronate liposomes or Csf1r antagonist (PLX5622) resulted in elevated cell death and diminished neuronal survival in excitotoxin-damaged retinas. Exogenous IL1β stimulated the proliferation and reactivity of Microglia in the absence of damage, reduced numbers of dying cells in damaged retinas, and increased neuronal survival following an insult. IL1β failed to provide neuroprotection in the IL-1R1-null retina, but IL1β-mediated neuroprotection was rescued when expression of IL-1R1 was restored in astrocytes. We conclude that reactive Microglia provide protection to retinal neurons, since the absence of Microglia is detrimental to survival. We propose that, at least in part, the survival-influencing effects of Microglia may be mediated by IL1β, IL-1R1, and interactions of Microglia and other macroglia.
Hiroshi Kitani - One of the best experts on this subject based on the ideXlab platform.
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possible roles of Microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models
Inflammation and Allergy - Drug Targets, 2009Co-Authors: Shuei Sugama, Takato Takenouchi, Makoto Hashimoto, Hiroshi KitaniAbstract:Microglia has been demonstrated to play critical roles in various neurodegenerative disorders, such as Parkinsons disease (PD), Alzheimers disease (AD), Huntingtons disease (HD) as well as neuroinflammatory disorders including AIDS encephalitis, multiple sclerosis. In this manuscript, we review the possible roles of Microglial cells in animal models of these clinical disorders and human clinical cases. Activated Microglia has been demonstrated in various brain regions, such as the hippocampus, substantia nigra and cortex in PD, AD and HD. The contribution of Microglial cells to these neurodegenerative disorders is supported by findings in animal experiments: (1) Microglial activation precedes the neurodegenerative changes; (2) activated Microglia surround the region that undergo neurodegeneration and phagocytose the degenerating cells; (3) activated Microglia release neurotoxic molecules such as interleukin(IL)-1β, IL-6, TNF-α, nitric oxide, reactive oxygen species; (4) inhibition of Microglial activation leads to the amelioration of neurodegeneration, (5) Microglia derived from aged animal exert more toxicity to neurons in an age-dependent fashion, in the same way neurodegenerative disorders occur. Although roles of activated Microglia in those clinical disorders needs to be further investigated, these findings suggest that Microglial cells may contribute to the progression of neurodegenerative changes as well as inflammation in the brain. Thus, the treatment to target Microglial inhibition may help to develop the pharmaceutical approaches for those clinical disorders.
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possible roles of Microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models
Inflammation and Allergy - Drug Targets, 2009Co-Authors: Shuei Sugama, Takato Takenouchi, Makoto Hashimoto, Byung Pil Cho, Tong H Joh, Hiroshi KitaniAbstract:Microglia has been demonstrated to play critical roles in various neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) as well as neuroinflammatory disorders including AIDS encephalitis, multiple sclerosis. In this manuscript, we review the possible roles of Microglial cells in animal models of these clinical disorders and human clinical cases. Activated Microglia has been demonstrated in various brain regions, such as the hippocampus, substantia nigra and cortex in PD, AD and HD. The contribution of Microglial cells to these neurodegenerative disorders is supported by findings in animal experiments: (1) Microglial activation precedes the neurodegenerative changes; (2) activated Microglia surround the region that undergo neurodegeneration and phagocytose the degenerating cells; (3) activated Microglia release neurotoxic molecules such as interleukin(IL)-1beta, IL-6, TNF-alpha, nitric oxide, reactive oxygen species; (4) inhibition of Microglial activation leads to the amelioration of neurodegeneration, (5) Microglia derived from aged animal exert more toxicity to neurons in an age-dependent fashion, in the same way neurodegenerative disorders occur. Although roles of activated Microglia in those clinical disorders needs to be further investigated, these findings suggest that Microglial cells may contribute to the progression of neurodegenerative changes as well as inflammation in the brain. Thus, the treatment to target Microglial inhibition may help to develop the pharmaceutical approaches for those clinical disorders.
George W Bell - One of the best experts on this subject based on the ideXlab platform.
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human ipsc derived Microglia assume a primary Microglia like state after transplantation into the neonatal mouse brain
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Devon S Svoboda, Inmaculada M Barrasa, Jian Shu, Rosalie Rietjens, Shupei Zhang, Maya Mitalipova, Peter Berube, Leonard D Shultz, George W BellAbstract:Microglia are essential for maintenance of normal brain function, with dysregulation contributing to numerous neurological diseases. Protocols have been developed to derive Microglia-like cells from human induced pluripotent stem cells (hiPSCs). However, primary Microglia display major differences in morphology and gene expression when grown in culture, including down-regulation of signature Microglial genes. Thus, in vitro differentiated Microglia may not accurately represent resting primary Microglia. To address this issue, we transplanted Microglial precursors derived in vitro from hiPSCs into neonatal mouse brains and found that the cells acquired characteristic Microglial morphology and gene expression signatures that closely resembled primary human Microglia. Single-cell RNA-sequencing analysis of transplanted Microglia showed similar cellular heterogeneity as primary human cells. Thus, hiPSCs-derived Microglia transplanted into the neonatal mouse brain assume a phenotype and gene expression signature resembling that of resting Microglia residing in the human brain, making chimeras a superior tool to study Microglia in human disease.