Reparative System Arising from CCR2(+) Monocyte Conversion Attenuates Neuroinflammation Following Ischemic Stroke

Park, Joo Hyun; Kim, Jong Youl; Kim, Yu Rim; Huang, Meirong; Chang, Ji Young; Sim, Adelene Y. L.; Jung, Hosung; Lee, Won Taek; Hyun, Young Youl; Lee, Jong Eun

doi:10.1007/s12975-020-00878-x

Cited by 16 publications

(17 citation statements)

References 60 publications

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“…We previously established that monocytes infiltrated into the parenchymal tissue of the injured brain, and these cells were converted to M2 phenotype macrophage by cytokine released from microglia, such as IL-4 and IL-13 ( 15 ). Following previous studies, in this study, we investigated the mechanism by which monocyte-derived macrophage infiltrated parenchymal brain tissue during neuroinflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent study demonstrated that pro-inflammatory monocytes migrate shortly after an ischemic stroke and are converted by interleukin (IL)-4 and IL-13 into anti-inflammatory macrophages that attenuate ischemic stroke ( 15 ). However, potential therapeutic targets that regulate the recruitment of monocyte-derived macrophage in neuroinflammation have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation

Kim

Huang

et al. 2022

Front. Immunol.

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Microglia, resident macrophages in the brain, play major roles in neuroinflammation after an acute many neurological diseases, including stroke. Our recent animal stroke model showed that interleukin (IL)-4 and IL-13 released by microglia are converted into monocyte-derived macrophages. However, the correlation with the migration mechanism of these cells is still unclear. This study aimed to clarify the effect of these cells on their migration and to identify potential targets that influence neuroinflammatory conditions. Inflammatory conditions were induced by lipopolysaccharide (LPS) treatment in in vitro and in vivo models. Cell migration was observed using transwell assay, and target chemokines were screened using the proteome profiler array in the in vitro model. Intravital, IVIS, and CLARITY imaging were used in the in vivo model. After LPS (1 ng/ml) treatment in BV2 (microglia cell line) and J774 (monocyte/macrophage cell line) cells, BV2 migration was approximately two-fold more enhanced compared to J774 migration. Overall, six types of chemokine C-C motif ligands (CCLs) were detected from the BV2 conditioned medium with LPS. These CCLs were related to C-C motif receptor (CCR)4 and CCR5. In the in vivo model, CCR4 and CCR5 antagonist significantly inhibited the migration of monocyte-derived macrophages to brain tissue following LPS (5 µg) treatment. In conclusion, the chemokines released by microglia may influence migration of monocyte-derived macrophages in necroinflammation conditions inducted by microglial activation. CCR4 and CCR5 expressed on monocyte-derived macrophages interacted with these chemokines and induced migration. Therefore, CCR4 and CCR5 may be explored as new therapeutic targets for neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation

Kim

Huang

et al. 2022

Front. Immunol.

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“…110 Based on the previous monocyte dichotomy, high CCR2 expression may indicate a pro-inflammatory monocyte cluster, potentially playing a negative pro-inflammatory role in the inflammatory cascade response of AIS and exacerbating brain damage. 107 Peripheral immune cells are considered as potential biomarkers of ischemic stroke. 111,112 Among the circulating immune cells, monocytes have been investigated as potential biomarkers.…”

Section: Monoc Y Te Smentioning

confidence: 99%

“…106 In mice, the monocytes can be divided into two distinct populations: pro-inflammatory monocytes expressing CCR2highCX3CR1low, which circulate in the blood, and anti-inflammatory monocytes expressing CCR2lowCX3CR1high, which patrol locally. 107 Park et al found that CCR2highCX3CR1low monocytes recruited to the injured brain undergo cell-dependent conversion to CCR2lowCX3CR1high monocytes, particularly under the influence of IL-13, thereby alleviating neuroinflammation after ischemic stroke. Thus, modulation of monocyte conversion is an important repair strategy for ischemic stroke.…”

Section: Monoc Y Te Smentioning

confidence: 99%

Perspective from single‐cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental?

Deng,

Hu,

Zhou

et al. 2023

CNS Neurosci Ther

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BackgroundAcute ischemic stroke (AIS) is a common cerebrovascular event associated with high incidence, disability, and poor prognosis. Studies have shown that various cell types, including microglia, astrocytes, oligodendrocytes, neurons, and neutrophils, play complex roles in the early stages of AIS and significantly affect its prognosis. Thus, a comprehensive understanding of the mechanisms of action of these cells will be beneficial for improving stroke prognosis. With the rapid development of single‐cell sequencing technology, researchers have explored the pathophysiological mechanisms underlying AIS at the single‐cell level.MethodWe systematically summarize the latest research on single‐cell sequencing in AIS.ResultIn this review, we summarize the phenotypes and functions of microglia, astrocytes, oligodendrocytes, neurons, neutrophils, monocytes, and lymphocytes, as well as their respective subtypes, at different time points following AIS. In particular, we focused on the crosstalk between microglia and astrocytes, oligodendrocytes, and neurons. Our findings reveal diverse and sometimes opposing roles within the same cell type, with the possibility of interconversion between different subclusters.ConclusionThis review offers a pioneering exploration of the functions of various glial cells and cell subclusters after AIS, shedding light on their regulatory mechanisms that facilitate the transformation of detrimental cell subclusters towards those that are beneficial for improving the prognosis of AIS. This approach has the potential to advance the discovery of new specific targets and the development of drugs, thus representing a significant breakthrough in addressing the challenges in AIS treatment.

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“…[ 14 ] Interleukin (IL), tumor necrosis factor-alpha (TNF-α), and MCP-1 are classic inflammatory factors released by macrophages, which further regulate the release and migration of inflammatory cells, such as neutrophils, natural killer cells, and lymphocytes. [ 15 ] The infiltration of inflammatory cells and cytokines, which were increased in the injured cerebral hemisphere, lead to greater cerebral I/R injury. [ 16 ]…”

Section: The Key Role Of Spleen In Ischemia/reperfusion Injurymentioning

confidence: 99%

Perspectives on effect of spleen in ischemic stroke

Ding

DeGracia

et al. 2022

Brain Circulation

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Despite decades of research, stroke therapies are limited to recanalization therapies that can only be used on <10% of stroke patients; the vast majority of stroke patients cannot be treated by these methods. Even if recanalization is successful, the outcome is often poor due to subsequent reperfusion injury. A major damage mechanism operating in stroke is inflammatory injury due to excessive pro-inflammatory cascades. Many studies have shown that, after stroke, splenic inflammatory cells, including neutrophils, monocytes/macrophages, and lymphocytes, are released and infiltrate the brain, heightening brain inflammation, and exacerbating ischemia/reperfusion injury. Clinical studies have observed spleen contraction in acute stroke patients where functional outcome improved with the gradual recovery of spleen volume. These observations are supported by stroke animal studies that have used splenectomy- or radiation-induced inhibition of spleen function to show spleen volume decrease during the acute phase of middle cerebral artery occlusion, and transfer of splenocytes to stroke-injured brain areas. Thus, activation and release of splenic cells are upstream of excessive brain inflammation in stroke. The development of reversible means of regulating splenic activity offers a therapeutic target and potential clinical treatment for decreasing brain inflammation and improving stroke outcomes.

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Reparative System Arising from CCR2(+) Monocyte Conversion Attenuates Neuroinflammation Following Ischemic Stroke

Cited by 16 publications

References 60 publications

CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation

CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation

Perspective from single‐cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental?

Perspectives on effect of spleen in ischemic stroke

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