Mechanisms and Potential Therapeutic Applications of Microglial Activation after Brain Injury

Kim, Jong Youl; Kim, Nuri; Yenari, Midori A.

doi:10.1111/cns.12360

Cited by 102 publications

(91 citation statements)

References 226 publications

(224 reference statements)

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“…Since all myeloid‐lineage cells express Iba1, including resident microglia, CNS border‐associated macrophages, and blood‐borne monocytes/macrophages, we could not differentiate between the contributions of activated resident microglia and monocyte‐derived macrophages to overall efferocytic activity. On the other hand, the bulk RNA‐seq on brain CD11b + CD45 high cells used in this study also could not distinguish between resident microglia that upregulate CD45 upon activation and monocyte‐derived macrophages, which have intrinsically high CD45 expression . Nevertheless, high expression of CD45 represents functionally active myeloid cells in the poststroke brain, and future studies may employ single‐cell RNA‐seq to further differentiate the roles of microglia versus macrophages.…”

Section: Discussionmentioning

confidence: 75%

“…On the other hand, the bulk RNA-seq on brain CD11b + CD45 high cells used in this study also could not distinguish between resident microglia that upregulate CD45 upon activation and monocyte-derived macrophages, which have intrinsically high CD45 expression. 50 Nevertheless, high expression of CD45 represents functionally active myeloid cells in the poststroke brain, and future studies may employ single-cell RNA-seq to further differentiate the roles of microglia versus macrophages. Microglia depletion approaches 51,52 may also shed light on the relative contribution to overall phagocytosis by CNS microglia and monocyte-derived macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

et al. 2019

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Aims Blood‐borne monocytes/macrophages infiltrate the brain in massive numbers after ischemic stroke, but their impact on poststroke brain injury and recovery remains elusive. This study examined the transcriptomic changes in monocytes/macrophages after ischemic stroke and the functional implications of these changes, particularly with regards to the contribution of these cells to the phagocytic clearance of dead/dying cells (efferocytosis) in the poststroke brain. Methods We performed whole‐genome RNA sequencing on the monocyte/macrophage population sorted from mouse brain and peripheral blood 5 days after permanent focal cerebral ischemia. In addition, the spatial and temporal profiles of macrophage efferocytosis were examined in vivo by immunohistochemistry 3‐7 days after brain ischemia. Results Robust transcriptomic changes occurred in monocytes/macrophages upon infiltrating the poststroke brain. Functional enrichment analysis revealed a transcriptome of brain macrophages that strongly favored efferocytic activity. A large number of efferocytosis‐related genes were upregulated in brain macrophages, the products of which are essential components involved in various steps of efferocytosis, such as chemotaxis, recognition of dead cells, engulfment, and processing of phagosomes. The efferocytic activity of brain macrophages were verified by immunohistochemistry, wherein Iba1‐labeled microglia/macrophages effectively cleared apoptotic neurons in the infarct during the subacute stage after brain ischemia. We also identified PPARγ and STAT6 as potential upstream regulators that shaped this proefferocytic and inflammation‐resolving transcriptome of macrophages in the poststroke brain. Conclusion Macrophages play a crucial role in the phagocytic clearance of dead neurons after ischemic stroke and promote the resolution of inflammation in the brain. Molecular therapies that enhance macrophage efferocytic capability may be promising treatments for ischemic stroke by facilitating inflammation resolution, brain repair, and recovery of neurological functions.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

et al. 2019

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“…However, in vivo, there is a wide range of microglial activation phenotypes that reflect the specific insult administered and the state of the surrounding NVU cells. Current research is investigating novel strategies to modulate microglial polarization as a potential therapeutic target (36,37).…”

Section: Microglia and Perivascular Macrophagesmentioning

confidence: 99%

The Translational Significance of the Neurovascular Unit

McConnell

Kersch

Woltjer

et al. 2017

Journal of Biological Chemistry

247

194

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Edited by Paul E. FraserThe mammalian brain is supplied with blood by specialized vasculature that is structurally and functionally distinct from that of the periphery. A defining feature of this vasculature is a physical blood-brain barrier (BBB). The BBB separates blood components from the brain microenvironment, regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. Over the last two decades, physiological studies of cerebral blood flow dynamics have demonstrated that substantial intercellular communication occurs between cells of the vasculature and the neurons and glia that abut the vasculature. These findings suggest that the BBB does not function independently, but as a module within the greater context of a multicellular neurovascular unit (NVU) that includes neurons, astrocytes, pericytes, and microglia as well as the blood vessels themselves. Here, we describe the roles of these NVU components as well as how they act in concert to modify cerebrovascular function and permeability in health and in select diseases.

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“…Traumatic brain injury (TBI) stimulates resident microglia to their activated form2829. Activated microglia undergo rapid proliferation and release pro-inflammatory signalling molecules, such as interleukin-1β (IL-1β), tumour necrosis factor α (TNFα), lymphotoxin, matrix metalloproteinases (MMPs), nitric oxide (NO) and other reactive oxygen species30, leading to astrocyte activation.…”

Section: Discussionmentioning

confidence: 99%

Inflammation-induced reversible switch of the neuron-specific enolase promoter from Purkinje neurons to Bergmann glia

Sawada¹,

Konno²,

Nagaoka³

et al. 2016

Sci Rep

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Neuron-specific enolase (NSE) is a glycolytic isoenzyme found in mature neurons and cells of neuronal origin. Injecting adeno-associated virus serotype 9 (AAV9) vectors carrying the NSE promoter into the cerebellar cortex is likely to cause the specific transduction of neuronal cells, such as Purkinje cells (PCs) and interneurons, but not Bergmann glia (BG). However, we found BG-predominant transduction without PC transduction along a traumatic needle tract for viral injection. The enhancement of neuroinflammation by the co-application of lipopolysaccharide (LPS) with AAV9 significantly expanded the BG-predominant area concurrently with the potentiated microglial activation. The BG-predominant transduction was gradually replaced by the PC-predominant transduction as the neuroinflammation dissipated. Experiments using glioma cell cultures revealed significant activation of the NSE promoter due to glucose deprivation, suggesting that intracellularly stored glycogen is metabolized through the glycolytic pathway for energy. Activation of the glycolytic enzyme promoter in BG concurrently with inactivation in PC may have pathophysiological significance for the production of lactate in activated BG and the utilization of lactate, which is provided by the BG-PC lactate shuttle, as a primary energy resource in injured PCs.

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Mechanisms and Potential Therapeutic Applications of Microglial Activation after Brain Injury

Cited by 102 publications

References 226 publications

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain

The Translational Significance of the Neurovascular Unit

Inflammation-induced reversible switch of the neuron-specific enolase promoter from Purkinje neurons to Bergmann glia

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