Developmental roles of microglia: A window into mechanisms of disease

Anderson, Sarah; Vetter, Monica L.

doi:10.1002/dvdy.1

Cited by 38 publications

(25 citation statements)

References 280 publications

(576 reference statements)

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“…Microglia are the resident immunocytes of the CNS; unlike other tissue macrophages, they persist for the life of the organism with negligible turnover rates at steady state (Tay et al, 2016;Anderson and Vetter, 2019). Microglia are instrumental in the maintenance of biochemical homeostasis, neuronal circuit maturation during development, and experience-dependent remodeling of neuronal circuits in the adult brain (Szepesi et al, 2018;Anderson and Vetter, 2019;Illes et al, 2019). The cellular processes of quiescent or ''resting'' microglia are highly mobile (extension and withdrawal) by scanning the environment for disruptions of brain homeostasis (Davalos et al, 2005).…”

Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R-or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans.

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Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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“…Both short-and long-term CNTF treatments further elevated the expression of genes involved in innate and adaptive immune systems, interferon, NF-kB, Jak-STAT, GPCR and MAPK signaling. Recent studies have shown a rapid and persistent activation of microglia in degenerating retinas, accompanied by significantly enhanced chemokine and cytokine gene upregulations [39][40][41][42] . Part of our RNA-seq data showing the uptick of immune system www.nature.com/scientificreports www.nature.com/scientificreports/ and chemokine gene expression may reflect microglia activities in the retina.…”

Section: Discussionmentioning

confidence: 99%

Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration

Wang

Rhee

Pellegrini

et al. 2020

Sci Rep

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ciliary neurotrophic factor (cntf) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, we performed high-throughput RnA sequencing analyses using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. In the absence of cntf treatment, transcriptome alterations were detected at the onset of rod degeneration compared with wild type mice, including reduction of key photoreceptor transcription factors Crx, Nrl, and rod phototransduction genes. Short-term CNTF treatments caused further declines of photoreceptor transcription factors accompanied by marked decreases of both rod-and cone-specific gene expression. in addition, cntf triggered acute elevation of transcripts in the innate immune system and growth factor signaling. These immune responses were sustained after long-term CNTF exposures that also affected neuronal transmission and metabolism. Comparisons of transcriptomes also uncovered common pathways shared with other retinal degeneration models. Cross referencing bulk RNA-seq with single-cell RnA-seq data revealed the cntf responsive cell types, including Müller glia, rod and cone photoreceptors, and bipolar cells. Together, these results demonstrate the influence of exogenous cntf on the retinal transcriptome landscape and illuminate likely cntf impacts in degenerating human retinas. Retinal degeneration (RD) is known as an irreversible, progressive neurologic disorder caused by genetic mutations and/or environmental or pathological damage to the retina. One therapeutic strategy to attenuate vision loss in disease conditions is treating the retina with neuroprotective agents that promote neuronal viability. Ciliary neurotrophic factor (CNTF) has been shown to be a potent neuroprotective agent for various types of retinal degenerations, including those caused by gene mutations, light-induced damage, and physical injury 1. Since CNTF enhances the survival of both photoreceptors and retinal ganglion cells, the two major cell classes damaged in retinal degenerative diseases, a CNTF-based therapy has been developed and tested in several clinical trials. To date, outcomes of the trials for retinitis pigmentosa, geographic atrophy, and achromatopsia have not demonstrated sufficient therapeutic benefits for human patients 2-5. However, CNTF therapy for macular telangiectasia type 2 has shown efficacy 6,7 , and a clinical trial for the second largest blinding disease glaucoma 8 is ongoing (https://clinicaltrials.gov/ct2/show/NCT01408472). To shed light on the molecular and cellular mechanisms of CNTF-mediated neuroprotection, we have delivered the same secreted recombinant CNTF used in human trials to a mouse model expressing the Rds/peripherin2 (Prph2) transgene with the P216L mutation 9. Pheripherin2 is a structural protein of the photoreceptor outer segment disc, and over 80 PRPH2 pathological mutations have been linked to RD, with...

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“…Ischemic blood supply disturbances of nervous tissue and other hypoxic states are the most common pathological condition of the central nervous system (CNS). Hypoxia of brain significantly reorganizes the CNS, changes the integrative-starting activity of neurons and leads to the formation of qualitatively new pattern of interaction between individual brain structures, and in the case of de-compensation of adaptation mechanisms, triggers a chain of pathological processes resulting in progressive neurological and cognitive disorders, including the development of encephalopathy [1][2][3][4][5][6]. Pharmacological action of existing neuroprotective agents consists mainly in protection or modulation of functions of mature cells of nervous tissue surviving in the pathology.…”

Section: Introductionmentioning

confidence: 99%

“…12,83±2,62 # 7,24±2,88 # 2,26±0,93 0,83±0,37 1,26±0,35 0,00±0,00 1,72±0,834 16,22±1,92 # 10,69±2,55 2,62±0,71 0,67±0,21 0,88±0,44 0,00±0,00 1,24±0,62 In the second period of the study(2-3 minute) 1 9,48±2,11 2,43±1,21 2,67±0,55 2,45±0,71 1,22±0,76 0,63±0,32 0,60±0,60 2 32,36±3,74 16,62±2,03 6,72±1,16 3,16±0,33 2,92±0,47 1,38±0,71 0,00±0,00 3 14,16±3,05# 9,39±1,67# 2,36±0,42# 1,78±0,54 1,99±0,50 0,56±0,55 0,72±0,37 4 12,21±2,42 6,16±2,25 2,93±1,12 0,66±0,12 1,31±0,62 0,83±0,51 0,89±0,52…”

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Halogenated (Cl-ion) songorine is a new original agonist of fibroblast growth factor receptors of neuronal-committed progenitors possessing neuroregenerative effect after cerebral ischemia and hypoxia in experimental animals

2019

Biointerface Res Appl Chem

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Alkaloids, which possess a stimulating effect on the functions of progenitors of various classes, were identified. The aim of this study was to identify mechanisms underlying development neuroregenerative effects of modified (halogenated (Cl-ion)) alkaloid songorine (mSON). To reveal the participation of neuronal-committed progenitors (clonogenic PSA-NCAM + cells) subventricular area of cerebral hemispheres (SVZ) in the realization of pharmacological action of this substance and to study the mechanisms of stimulating their functions under the influence of mSON. mSON was received by halogenation (Cl-) of alkaloid and administered to the experimental animals after modeling cerebral ischemia (rats) and posthypoxic encephalopathy (mice). Therapeutic effects of mSON were assessed with the help of functional and morphological methods. To study the effect of mSON on clonogenic PSA-NCAM + cells, the role of receptors to the growth factor of fibroblasts (FGFR) and intracellular signaling molecules of neuronal-committed progenitors in their implementation. Normalization of behavior and reflexive activity on the background of significant correction of morphological pattern malfunctions in the brain of experimental animals during mSON administration after modeling of brain pathology was revealed. The increase in the number of clonogenic PSA-NCAM + cells in SVZ was determined. It was shown a direct stimulating effect of mSON on neuronal-committed progenitors, which was abolished by the addition of anti-FGFR. Significant differences in intracellular signaling in clonogenic PSA-NCAM + cells while stimulating their functions with mSON and growth factor of fibroblasts were determined. These results suggested that mSON is a new original agonist of neuronal-committed progenitors FGFR. mSON is a promising one for the development of a safe and highly effective drug for neurological practice.

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Developmental roles of microglia: A window into mechanisms of disease

Cited by 38 publications

References 280 publications

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration

Halogenated (Cl-ion) songorine is a new original agonist of fibroblast growth factor receptors of neuronal-committed progenitors possessing neuroregenerative effect after cerebral ischemia and hypoxia in experimental animals

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