Characterizing microglial gene expression in a model of secondary progressive multiple sclerosis

Vainchtein, Ilia D.; Alsema, Astrid M.; Dubbelaar, Marissa L.; Grit, Corien; Vinet, Jonathan; Weering, Hilmar R. J. van; Al-Izki, Sarah; Biagini, Giuseppe; Brouwer, Nieske; Amor, Sandra; Baker, David; Eggen, Bart J. L.; Boddeke, Erik; Kooistra, Susanne M.

doi:10.1002/glia.24297

Cited by 4 publications

(2 citation statements)

References 99 publications

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“…Recently, allopregnanolone properties have been characterized in cultured BV2 microglial cells and also in primary microglia cultures, disclosing an array of modulatory effects on phagocytosis and morphology, which markedly changed in the experimental conditions able to reproduce the interruption of the blood–brain barrier functions, as it occurs in several neurological disorders characterized by neuroinflammation [ 24 ]. Indeed, microglia are a major player not only in protecting the brain from aggression by pathogens [ 25 ], but also in mediating neuroinflammation [ 26 ], especially when the inflammatory process becomes chronic [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Human Microglia Synthesize Neurosteroids to Cope with Rotenone-Induced Oxidative Stress

et al. 2023

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We obtained evidence that mouse BV2 microglia synthesize neurosteroids dynamically to modify neurosteroid levels in response to oxidative damage caused by rotenone. Here, we evaluated whether neurosteroids could be produced and altered in response to rotenone by the human microglial clone 3 (HMC3) cell line. To this aim, HMC3 cultures were exposed to rotenone (100 nM) and neurosteroids were measured in the culture medium by liquid chromatography with tandem mass spectrometry. Microglia reactivity was evaluated by measuring interleukin 6 (IL-6) levels, whereas cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After 24 h (h), rotenone increased IL-6 and reactive oxygen species levels by approximately +37% over the baseline, without affecting cell viability; however, microglia viability was significantly reduced at 48 h (p < 0.01). These changes were accompanied by the downregulation of several neurosteroids, including pregnenolone, pregnenolone sulfate, 5α-dihydroprogesterone, and pregnanolone, except for allopregnanolone, which instead was remarkably increased (p < 0.05). Interestingly, treatment with exogenous allopregnanolone (1 nM) efficiently prevented the reduction in HMC3 cell viability. In conclusion, this is the first evidence that human microglia can produce allopregnanolone and that this neurosteroid is increasingly released in response to oxidative stress, to tentatively support the microglia’s survival.

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Section: Introductionmentioning

confidence: 99%

Human Microglia Synthesize Neurosteroids to Cope with Rotenone-Induced Oxidative Stress

et al. 2023

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“…The advent of single cell omics has made it clear that microglial responses are highly heterogeneous and vary in time and space depending on the type, severity, and localization of injury/disease within the CNS. This has led to the identification of multiple coexisting microglial phenotypes with distinct and often opposite functions ( Zheng et al, 2022 ; Vainchtein et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Peripherally derived myeloid cells induce disease-dependent phenotypic changes in microglia

Thougaard,

Carney,

Wlodarczyk

et al. 2023

Front. Cell. Neurosci.

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In central nervous system (CNS) injury and disease, peripherally derived myeloid cells infiltrate the CNS parenchyma and interact with resident cells, propagating the neuroinflammatory response. Because peripheral myeloid populations differ profoundly depending on the type and phase of injury, their crosstalk with CNS resident cells, particularly microglia, will lead to different functional outcomes. Thus, understanding how peripheral myeloid cells affect the phenotype and function of microglia in different disease conditions and phases may lead to a better understanding of disease-specific targetable pathways for neuroprotection and neurorepair. To this end, we set out to develop an in vitro system to investigate the communication between peripheral myeloid cells and microglia, with the goal of uncovering potential differences due to disease type and timing. We isolated peripheral myeloid cells from mice undergoing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, or acute cerebral ischemia by permanent middle cerebral artery occlusion (pMCAO) at different times after disease and probed their ability to change the phenotype of primary microglia isolated from the brain of adult mice. We identified changes not only dependent on the disease model, but also on the timepoint after disease onset from which the myeloid cells were isolated. Peripheral myeloid cells from acute EAE induced morphological changes in microglia, followed by increases in expression of genes involved in inflammatory signaling. Conversely, it was the peripheral myeloid cells from the chronic phase of pMCAO that induced gene expression changes in genes involved in inflammatory signaling and phagocytosis, which was not followed by a change in morphology. This underscores the importance of understanding the role of infiltrating myeloid cells in different disease contexts and phases. Furthermore, we showed that our assay is a valuable tool for investigating myeloid cell interactions in a range of CNS neuroinflammatory conditions.

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Characterizing microglial gene expression in a model of secondary progressive multiple sclerosis

Vainchtein

Alsema

Dubbelaar

et al. 2022

Glia

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Multiple sclerosis (MS) is the most common inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. Chronicrelapsing experimental autoimmune encephalomyelitis (crEAE) in Biozzi ABH mice is an experimental model of MS. This crEAE model is characterized by an acute phase with severe neurological disability, followed by remission of disease, relapse of neurological disease and remission that eventually results in a chronic progressive phase that mimics the secondary progressive phase (SPEAE) of MS. In both MS and SPEAE, the role of microglia is poorly defined. We used a crEAE model to characterize microglia in the different phases of crEAE phases using morphometric and RNA sequencing analyses. At the initial, acute inflammation phase, microglia acquired a proinflammatory phenotype. At the remission phase, expression of standard immune activation genes was decreased while expression of genes associated with lipid metabolism and tissue remodeling were increased. Chronic phase microglia partially regain inflammatory gene sets and increase expression of genes associated with proliferation. Together, the data presented here indicate that microglia obtain different features at different stages of crEAE and a particularly mixed phenotype in the chronic stage. Understanding the properties of microglia that are present at the chronic phase of EAE will help to understand the role of microglia in secondary progressive MS, to better aid the development of therapies for this phase of the disease.

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Characterizing microglial gene expression in a model of secondary progressive multiple sclerosis

Cited by 4 publications

References 99 publications

Human Microglia Synthesize Neurosteroids to Cope with Rotenone-Induced Oxidative Stress

Human Microglia Synthesize Neurosteroids to Cope with Rotenone-Induced Oxidative Stress

Peripherally derived myeloid cells induce disease-dependent phenotypic changes in microglia

Characterizing microglial gene expression in a model of secondary progressive multiple sclerosis

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