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1.
Nat Rev Neurosci ; 24(7): 397-415, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37268822

RESUMEN

As resident macrophages of the CNS, microglia are critical immune effectors of inflammatory lesions and associated neural dysfunctions. In multiple sclerosis (MS) and its animal models, chronic microglial inflammatory activity damages myelin and disrupts axonal and synaptic activity. In contrast to these detrimental effects, the potent phagocytic and tissue-remodelling capabilities of microglia support critical endogenous repair mechanisms. Although these opposing capabilities have long been appreciated, a precise understanding of their underlying molecular effectors is only beginning to emerge. Here, we review recent advances in our understanding of the roles of microglia in animal models of MS and demyelinating lesions and the mechanisms that underlie their damaging and repairing activities. We also discuss how the structured organization and regulation of the genome enables complex transcriptional heterogeneity within the microglial cell population at demyelinating lesions.


Asunto(s)
Esclerosis Múltiple , Animales , Microglía/fisiología , Macrófagos , Axones/patología , Inflamación/patología , Modelos Animales de Enfermedad
2.
Glia ; 70(3): 572-589, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34862814

RESUMEN

Microglia proliferate during brain development and brain lesions, but how this is coordinated at the transcriptional level is not well understood. Here, we investigated fundamental aspects of the transcriptional process associated with proliferation of mouse microglia during postnatal development and in adults in a model of induced microglial depletion-repopulation. While each proliferative subset displayed globally a distinct signature of gene expression, they also co-expressed a subgroup of 1370 genes at higher levels than quiescent microglia. Expression of these may be coordinated by one of two mechanisms of regulation with distinct properties. A first mechanism augments expression of genes already expressed in quiescent microglia and is subject to regulation by Klf/Sp, Nfy, and Ets transcription factors. Alternatively, a second mechanism enables de novo transcription of cell cycle genes and requires additional regulatory input from Lin54 and E2f transcription factors. Of note, transcriptional upregulation of E2f1 and E2f2 family members may represent a critical regulatory checkpoint to enable microglia to achieve efficient cell cycling. Furthermore, analysis of the activity profile of the repertoire of promoter-distal genomic regulatory elements suggests a relatively restricted role for these elements in coordinating cell cycle gene expression in microglia. Overall, proliferating microglia integrates regulation of cell cycle gene expression with their broader, context-dependent, transcriptional landscape.


Asunto(s)
Regulación de la Expresión Génica , Microglía , Animales , Proliferación Celular/genética , Ratones , Microglía/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
Front Cell Dev Biol ; 9: 729338, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34604228

RESUMEN

The modification of histones-the structural components of chromatin-is a central topic in research efforts to understand the mechanisms regulating genome expression and stability. These modifications frequently occur through associations with multisubunit complexes, which contain active enzymes and additional components that orient their specificity and read the histone modifications that comprise epigenetic signatures. To understand the functions of these modifications it is critical to study the enzymes and substrates involved in their native contexts. Here, we describe experimental approaches to purify native chromatin modifiers complexes from mammalian cells and to produce recombinant nucleosomes that are used as substrates to determine the activity of the complex. In addition, we present a novel approach, similar to the yeast anchor-away system, to study the functions of essential chromatin modifiers by quickly inducing their depletion from the nucleus. The step-by-step protocols included will help standardize these approaches in the research community, enabling convincing conclusions about the specificities and functions of these crucial regulators of the eukaryotic genome.

4.
J Neurosci ; 41(15): 3366-3385, 2021 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-33712513

RESUMEN

Excessive inflammation within the CNS is injurious, but an immune response is also required for regeneration. Macrophages and microglia adopt different properties depending on their microenvironment, and exposure to IL4 and IL13 has been used to elicit repair. Unexpectedly, while LPS-exposed macrophages and microglia killed neural cells in culture, the addition of LPS to IL4/IL13-treated macrophages and microglia profoundly elevated IL10, repair metabolites, heparin binding epidermal growth factor trophic factor, antioxidants, and matrix-remodeling proteases. In C57BL/6 female mice, the generation of M(LPS/IL4/IL13) macrophages required TLR4 and MyD88 signaling, downstream activation of phosphatidylinositol-3 kinase/mTOR and MAP kinases, and convergence on phospho-CREB, STAT6, and NFE2. Following mouse spinal cord demyelination, local LPS/IL4/IL13 deposition markedly increased lesional phagocytic macrophages/microglia, lactate and heparin binding epidermal growth factor, matrix remodeling, oligodendrogenesis, and remyelination. Our data show that a prominent reparative state of macrophages/microglia is generated by the unexpected integration of pro- and anti-inflammatory activation cues. The results have translational potential, as the LPS/IL4/IL13 mixture could be locally applied to a focal CNS injury to enhance neural regeneration and recovery.SIGNIFICANCE STATEMENT The combination of LPS and regulatory IL4 and IL13 signaling in macrophages and microglia produces a previously unknown and particularly reparative phenotype devoid of pro-inflammatory neurotoxic features. The local administration of LPS/IL4/IL13 into spinal cord lesion elicits profound oligodendrogenesis and remyelination. The careful use of LPS and IL4/IL13 mixture could harness the known benefits of neuroinflammation to enable repair in neurologic insults.


Asunto(s)
Macrófagos/metabolismo , Microglía/metabolismo , Vaina de Mielina/metabolismo , Transducción de Señal , Regeneración de la Medula Espinal , Médula Espinal/metabolismo , Animales , Células Cultivadas , Técnicas de Cocultivo/métodos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Femenino , Inflamación , Interleucina-13/farmacología , Interleucina-4/farmacología , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/metabolismo , Subunidad p45 del Factor de Transcripción NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Transcripción STAT6/metabolismo , Médula Espinal/patología , Médula Espinal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Receptor Toll-Like 4/metabolismo
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