Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke

Lee, Youngjeon; Lee, Sang-Rae; Choi, Sung Sik; Yeo, Hyeon-Gu; Chang, Kyu‐Tae; Lee, Hong J.

doi:10.1155/2014/297241

Cited by 110 publications

(98 citation statements)

References 76 publications

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“…However, sex differences in microglia responses to ischemia are largely unknown. Microglia phagocytosis, initiated in part by CD11b-ligand interactions, is a double-edged sword; necessary for wound healing but also well documented in pre-clinical research as a source of secondary inflammatory injury after stroke (Brown and Neher, 2012; Lee et al, 2014). Understanding this balance in both males and females is relevant to future stroke therapies which are developed to promote brain recovery and yet must also account for inherent secondary injury.…”

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confidence: 99%

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

Morrison

Filosa

2016

Neuroscience

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Epidemiological studies report that infarct size is decreased and stroke outcomes are improved in young females when compared to males. However, mechanistic insight is lacking. We posit that sex-specific differences in glial cell functions occurring immediately after ischemic stroke are a source of dichotomous outcomes. In this study we assessed astrocyte Ca2+ dynamics, aquaporin 4 (AQP4) polarity, S100β expression pattern, as well as, microglia morphology and phagocytic marker CD11b in male and female mice following 60 minutes of middle cerebral artery (MCA) occlusion. We reveal sex differences in the frequency of intracellular astrocyte Ca2+ elevations (F(1,86)=8.19, P=0.005) and microglia volume (F(1,40)=12.47, P=0.009) immediately following MCA occlusion in acute brain slices. Measured in fixed tissue, AQP4 polarity was disrupted (F(5,86)=3.30, P=0.009) and the area of non-S100β immunoreactivity increased in ipsilateral brain regions after 60 min of MCA occlusion (F(5,86)=4.72, P=0.007). However, astrocyte changes were robust in male mice when compared to females. Additional sex differences were discovered regarding microglia phagocytic receptor CD11b. In sham mice, constitutively high CD11b immunofluorescence was observed in females when compared to males (P=0.03). When compared to sham, only male mice exhibited an increase in CD11b immunoreactivity after MCA occlusion (P=0.006). We posit that a sex difference in the presence of constitutive CD11b has a role in determining male and female microglia phagocytic responses to ischemia. Taken together, these findings are critical to understanding potential sex differences in glial physiology as well as stroke pathobiology which are foundational for the development of future sex-specific stroke therapies.

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confidence: 99%

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

Morrison

Filosa

2016

Neuroscience

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“…In contrast, blood-derived macrophages are rare on day 2, as they infiltrate the damaged brain tissue 24-48 hours after focal cerebral. In their activated status in the penumbra, these cells shift from a thin, ramified morphology to a large, amoeboid structure, reflecting their activation (Lee et al, 2014;Ritzel et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory cell populations in early neuroinflammation in the core and peri-ischemic lesions of rat brain after transient focal cerebral ischemia: A morphometric study

Horváth

Orădan

Chiriac

et al. 2018

Preprint

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Background and Objective:Clinical and experimental observations emphasize the role of inflammation as a direct risk factor for stroke. To better characterize the inflammation, we have conducted a detailed histological analysis of the inflammatory cell population after transient middle cerebral artery occlusion in a rat model. Methods:Fifteen adult Wistar male rats were divided randomly into test (n=10) and sham (n=5) groups. In the ischemic group, transient focal cerebral ischemia was induced with an intraluminal filament technique. Histologic lesions of the ischemic core and the surrounding penumbra zone were evaluated, based on a complex algorithm. Representative morphological changes in the core and the penumbra zone were compared. Immunohistochemistry was performed for leukocytes markers (CD15, CD68, CD3), leukocyte-released effectors (MMP-9 and COX-2), and FXIII (possibly involved in microglia and macrophage activation)Results: Neuronal vacuolation and degeneration were significantly more in the core lesion, whereas cellular edema and inflammatory infiltrate were increased in the penumbra. CD68, CD3, FXIII and Cox-2 expression were significantly higher in the penumbra than in the core (p=0.026; p=0.006; p=0.002; and p<0.001).Discussion: In the rat model of middle cerebral artery occlusion, inflammatory mechanisms, microglia/macrophage cells, and T-lymphocytes likely play an important role in the penumbra. The deterioration of neurons is less in the penumbra than in the core. Appreciation of the role of the inflammatory cells and mechanisms involved in stroke might lead to measures to inhibit the injury and save brain volume. ABSTRACT Background and Objective: Clinical and experimental observations emphasize the role of inflammation as a direct risk factor for stroke. To better characterize the inflammation, we have conducted a detailed histological analysis of the inflammatory cell population after transient middle cerebral artery occlusion in a rat model.

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“…In the dMCAO model, resident neurons and microglia cells, which do not completely die, and macrophages that migrate into the ischemic core may be responsible for the recovery of the damaged brain. Microglia and macrophages are the main components of neuro-inflammation and are believed to elicit secondary injury of stroke [14, 15]. However, a growing body of research has provided support for dual roles for microglia and macrophages, both beneficial and harmful.…”

Section: Introductionmentioning

confidence: 99%

Intravenously Delivered Allogeneic Mesenchymal Stem Cells Bidirectionally Regulate Inflammation and Induce Neurotrophic Effects in Distal Middle Cerebral Artery Occlusion Rats Within the First 7 Days After Stroke

Huang

Zhao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Neurotrophic effects and immunosuppression are the main therapeutic mechanisms of mesenchymal stem cells (MSCs) in stroke treatment. Neurotrophins are produced by graft cells, host neurons, astrocytes, and even microglia/macrophages. Meanwhile, MSCs can increase inflammation if they are not sufficiently induced by pro-inflammatory cytokines. We examined whether intravenously transplanted bone marrow MSCs (BM-MSCs) increase inflammation in distal middle cerebral artery occlusion (dMCAO) rats, how long the increased inflammation effect persists for, and what the final therapeutic outcomes will be. We also tested the neurotrophic role of BM-MSCs and attempted to identify the neurotrophin-producing cells. Methods: At 1 h after dMCAO was performed on Sprague-Dawley rats, allogeneic BM-MSCs were transplanted intravenously. The infarct volume was examined by Tetrazolium Red staining at 2 days (day 2), and the behavioral tests (cylinder test and grid walking test) were performed at 2, 4 (day 4) and 7 days (day 7) after transplantation. The concentrations of inflammation related cytokines and neurotrophins in the ischemic cortex, ipsilateral striatum, and serum, were measured using ELISA at days 2-7. The cell source of neurotrophins was observed by immunohistochemistry. Results: The transplanted cells were mainly found in the infarct border zone (IBZ) of the brain. Infarct volume was reduced and behavioral outcomes were improved at 2 days after ischemia. In the striatum and circulation, BM-MSC transplantation increased inflammation at day 2 and decreased it at day 7. At days 2-7, insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) concentrations in the ischemic core of the cortex were significantly higher in the BM-MSC group than in the ischemia vehicle group. IGF-1 and BDNF were derived mainly from host microglia/macrophages in the ischemic core, and transplanted cells in the IBZ. At day 2, BM-MSC transplantation significantly increased the number of IGF-1⁺CD68⁺ and BDNF⁺Iba-1⁺ double positive cells in the ischemic core cortex. Conclusions: Although increased inflammation, BM-MSCs were still beneficial to dMCAO recovery at day 2. The immunopromoting effect of MSCs was transient and shifted to an immunosuppressive action at day 7. The neurotrophic factors IGF-1 and BDNF, which were mainly derived from transplanted BM-MSCs and host microglia/macrophages, contributed to the therapeutic effects from day 2 to day 7.

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Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke

Cited by 110 publications

References 76 publications

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

Inflammatory cell populations in early neuroinflammation in the core and peri-ischemic lesions of rat brain after transient focal cerebral ischemia: A morphometric study

Intravenously Delivered Allogeneic Mesenchymal Stem Cells Bidirectionally Regulate Inflammation and Induce Neurotrophic Effects in Distal Middle Cerebral Artery Occlusion Rats Within the First 7 Days After Stroke

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