Microglial modulation through colony‐stimulating factor‐1 receptor inhibition attenuates demyelination

Mancini, Victoria Sofia Berenice Wies; Pasquini, Juana M.; Correale, Jorge; Pasquini, Laura

doi:10.1002/glia.23540

Cited by 34 publications

(23 citation statements)

References 85 publications

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“…4) demonstrating an unequivocal requirement for microglia in driving CUP-dependent demyelination. These results agree with recent reports in which other CSF1 inhibitors used to deplete microglia resulted in a delay of demyelination mediated by cuprizone (Beckmann, et al, 2018;Wies Mancini, Pasquini, Correale, & Pasquini, 2018) and EAE (Nissen, et al, 2018) further demonstrating the significance of microglia activation as crucial contributors to disease progression.…”

Section: Microglia Are Necessary For Demyelination In the Cuprizone Msupporting

confidence: 93%

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Marzan

West²,

Salzer

2018

Preprint

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Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS). The precise role of microglia during demyelination, and the relative contributions of microglia vs. peripheral macrophages, are incompletely understood. Here, using a genetic fate mapping strategy, we identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Pharmacological depletion of microglia demonstrates these cells are necessary for the demyelination, loss of oligodendrocytes, and reactive astrocytosis normally evident in this model. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these damaged myelin sheaths are lost upon-repopulation of microglia.Injection of colony-stimulating factor-1 to drive focal microgliosis in white matter is sufficient to induce focal demyelination in vivo. These studies indicate activated microglia are required for demyelination that results from primary myelin pathology and are sufficient to induce demyelination directly.Stem Cell and the NIH. DM was a recipient of an NRSA fellowship from NINDS.

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Section: Microglia Are Necessary For Demyelination In the Cuprizone Msupporting

confidence: 93%

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Marzan

West²,

Salzer

2018

Preprint

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“…Microglia and monocytes play significant roles in demyelination and the success of myelin regeneration (Miron et al, 2013;Lloyd et al, 2019;Wies Mancini et al, 2019), and indeed direct proinflammatory and prorepair astrocyte properties (Skripuletz et al, 2013;Liddelow et al, 2017). After 6 weeks of cuprizone demyelination, the robust increases in microglial Iba1 were reduced in PAR1 knock-outs.…”

Section: Blocking Par1 Promotes Remyelination Through Possible Opc-inmentioning

confidence: 99%

Blocking the Thrombin Receptor Promotes Repair of Demyelinated Lesions in the Adult Brain

et al. 2020

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Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knockout of the thrombin receptor, also known as Protease Activated Receptor 1 (PAR1), accelerates myelin development. Here we demonstrate that knocking out PAR1 also promotes myelin regeneration. Outcomes in two unique models of myelin injury and repair, that is lysolecithin or cuprizone-mediated demyelination, showed that PAR1 knockout in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knockout mice occurred in tandem with a skewing of reactive astrocyte signatures toward a prorepair phenotype. In cell culture, the promyelinating effects of PAR1 loss of function are consistent with possible direct effects on the myelinating potential of oligodendrocyte progenitor cells (OPCs), in addition to OPC-indirect effects involving enhanced astrocyte expression of promyelinating factors, such as BDNF. These findings highlight previously unrecognized roles of PAR1 in myelin regeneration, including integrated actions across the oligodendrocyte and astroglial compartments that are at least partially mechanistically linked to the powerful BDNF-TrkB neurotrophic signaling system. Altogether, findings suggest PAR1 may be a therapeutically tractable target for demyelinating disorders of the CNS.

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“…The CSF1R kinase inhibitor BLZ945 prophylactically and therapeutically prevents demyelination in the cuprizone model, namely in the corpus callosum. However, it increases myelin debris and axonal damage in other fiber tracts reminding the phenotype observed in cuprizone-treated TREM2 knock-out mice (Beckmann et al, 2018;Wies Mancini et al, 2019). Although TNF is a master pro-inflammatory product of activated microglia/macrophages implicated in CNS demyelination, the blockade of its soluble form did not prevent cuprizone-induced oligodendrocyte loss and demyelination, but led to efficient early remyelination due to improved phagocytosis of myelin debris and resolution of microglia/macrophage activation (Karamita et al, 2017).…”

Section: Therapeutic Modulation Of Microglia/macrophagesmentioning

confidence: 99%

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

Traiffort

Kassoussi

Zahaf

et al. 2020

Front. Cell. Neurosci.

139

108

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Myelination is an essential process that consists of the ensheathment of axons by myelin. In the central nervous system (CNS), myelin is synthesized by oligodendrocytes. The proliferation, migration, and differentiation of oligodendrocyte precursor cells constitute a prerequisite before mature oligodendrocytes extend their processes around the axons and progressively generate a multilamellar lipidic sheath. Although myelination is predominately driven by oligodendrocytes, the other glial cells including astrocytes and microglia, also contribute to this process. The present review is an update of the most recent emerging mechanisms involving astrocyte and microglia in myelin production. The contribution of these cells will be first described during developmental myelination that occurs in the early postnatal period and is critical for the proper development of cognition and behavior. Then, we will report the novel findings regarding the beneficial or deleterious effects of astroglia and microglia, which respectively promote or impair the endogenous capacity of oligodendrocyte progenitor cells (OPCs) to induce spontaneous remyelination after myelin loss. Acute delineation of astrocyte and microglia activities and cross-talk should uncover the way towards novel therapeutic perspectives aimed at recovering proper myelination during development or at breaking down the barriers impeding the regeneration of the damaged myelin that occurs in CNS demyelinating diseases.

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Microglial modulation through colony‐stimulating factor‐1 receptor inhibition attenuates demyelination

Cited by 34 publications

References 85 publications

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Blocking the Thrombin Receptor Promotes Repair of Demyelinated Lesions in the Adult Brain

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

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