Microglia/macrophage diversities in central nervous system physiology and pathology

Xie, Di; He, Maxine; Hu, Xiaoming

doi:10.1111/cns.13257

Cited by 17 publications

(22 citation statements)

References 43 publications

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“…17 Microglia are highly dynamic cells that interact with other cells via direct (physical cell-cell touch) or indirect (release of soluble molecules) mechanisms. 22,78 Our transcriptional profiling data suggest that the capabilities to interact and activate surrounding cells are remarkably dampened in aged microglia after cerebral ischemia. Gene clusters with functional implications for cellular activation are strongly activated in young microglia, but not in aged microglia, after ischemic stroke.…”

Section: Discussionmentioning

confidence: 90%

Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia

Shi

Rocha

Zhang

et al. 2020

J Cereb Blood Flow Metab

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Senescence-associated alterations in microglia may have profound impact on cerebral homeostasis and stroke outcomes. However, the lack of a transcriptome-wide comparison between young and aged microglia in the context of ischemia limits our understanding of aging-related mechanisms. Herein, we performed RNA sequencing analysis of microglia purified from cerebral hemispheres of young adult (10-week-old) and aged (18-month-old) mice five days after distal middle cerebral artery occlusion or after sham operation. Considerable transcriptional differences were observed between young and aged microglia in healthy brains, indicating heightened chronic inflammation in aged microglia. Following stroke, the overall transcriptional activation was more robust (>13-fold in the number of genes upregulated) in young microglia than in aged microglia. Gene clusters with functional implications in immune inflammatory responses, immune cell chemotaxis, tissue remodeling, and cell-cell interactions were markedly activated in microglia of young but not aged stroke mice. Consistent with the genomic profiling predictions, post-stroke cerebral infiltration of peripheral immune cells was markedly decreased in aged mice compared to young mice. Moreover, post-ischemic aged microglia demonstrated reduced interaction with neighboring neurons and diminished polarity toward the infarct lesion. These alterations in microglial gene response and behavior may contribute to aging-driven vulnerability and poorer recovery after ischemic stroke.

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Section: Discussionmentioning

confidence: 90%

Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia

Shi

Rocha

Zhang

et al. 2020

J Cereb Blood Flow Metab

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“…Depending upon the context, however, the depletion of microglia may generate opposing impacts—beneficial or detrimental—on post-stroke injury and repair. 2,5–7 These collective observations highlight the dynamic and diverse roles of microglia in response to distinct microenvironmental cues in the ischemic brain.…”

Section: Introductionmentioning

confidence: 94%

“…Aside from their established roles as immune sentinels, microglia perform a range of homeostatic activities to maintain normal CNS functions. 1,2 In an injured or diseased brain, resident microglia, as well as infiltrating macrophages, serve as the first line of defense and play diverse roles in debris clearance, inflammation induction and resolution, trophic factor release and neuroregeneration. Indeed, clinical studies reveal prompt and persistent activation of microglia up to months after ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged microglia during stroke recovery

Jiang

et al. 2020

J Cereb Blood Flow Metab

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Age-dependent alterations in microglia behavior have been implicated in neurodegeneration and CNS injuries. Here, we compared the transcriptional profiles of young versus aged microglia during stroke recovery. CD45intermediateCD11b+ microglia were FACS-isolated from the brains of young (10-week-old) and aged (18-month-old) male mice with sham operation or 14 days after distal middle cerebral artery occlusion and subjected to RNA-sequencing analysis. Functional groups enriched in young microglia are indicative of upregulation in cell movement, cell interactions, inflammatory responses and angiogenesis, while aged microglia exhibited a reduction or no change in these features. We confirmed reduced chemoattractive capacities of aged microglia toward ischemic brain tissue in organotypic slide co-cultures, and delayed accumulation of aged microglia around dead neurons injected into the striatum in vivo. In addition, aging is associated with an overall failure to increase the expression of microglial genes involved in cell–cell interactions, such as CXCL10. Finally, impaired upregulation of pro-angiogenic genes in aged microglia was associated with a decline in neovascularization in aged mice compared to young mice after distal middle cerebral artery occlusion. This study provides a new resource to understand the mechanisms underlying microglial alterations in the aged brain milieu and sheds light on new strategies to improve microglial functions in aged stroke victims.

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“…Microglia, the resident immune cells of the CNS, are widely distributed across the brain and spinal cord and form an integral part of the neurovascular unit. One of the major functions of microglia is to constantly survey the CNS microenvironment and maintain brain homeostasis 7,8 . Stroke injury induces rapid activation and migration of microglia to the lesion sites 9 .…”

Section: Introductionmentioning

confidence: 99%

Microglial/Macrophage polarization and function in brain injury and repair after stroke

et al. 2021

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Stroke is a leading cause of disability and mortality, with limited treatment options. After stroke injury, microglia and CNS‐resident macrophages are rapidly activated and regulate neuropathological processes to steer the course of functional recovery. To accelerate this recovery, microglia can engulf dying cells and clear irreparably‐damaged tissues, thereby creating a microenvironment that is more suitable for the formation of new neural circuitry. In addition, monocyte‐derived macrophages cross the compromised blood‐brain barrier to infiltrate the injured brain. The specific functions of myeloid lineage cells in brain injury and repair are diverse and dependent on phenotypic polarization statuses. However, it remains to be determined to what degree the CNS‐invading macrophages occupy different functional niches from CNS‐resident microglia. In this review, we describe the physiological characteristics and functions of microglia in the developing and adult brain. We also review (a) the activation and phenotypic polarization of microglia and macrophages after stroke, (b) molecular mechanisms that control polarization status, and (c) the contribution of microglia to brain pathology versus repair. Finally, we summarize current breakthroughs in therapeutic strategies that calibrate microglia/macrophage responses after stroke.

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Microglia/macrophage diversities in central nervous system physiology and pathology

Cited by 17 publications

References 43 publications

Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia

Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia

Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged microglia during stroke recovery

Microglial/Macrophage polarization and function in brain injury and repair after stroke

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