Inflammatory mechanisms in ischemic stroke: role of inflammatory cells

Jin, Rong; Yang, Guoren; Li, Guohong

doi:10.1189/jlb.1109766

Cited by 1,339 publications

(1,088 citation statements)

References 117 publications

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“…Mechanism which CN‐105 reduced early mortality were likely through decreasing overall infarct size, as observed in our study, and also through decreasing cerebral edema by maintaining BBB integrity. Inflammation begins within hours in the postischemic brain,74, 75 resulting in activation of microglial and secretion of inflammatory cytokines within 24 h of infarction 76. These inflammatory cytokines contributes to cerebral edema through disruption of BBB integrity 77.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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“…The trafficking of immune cells in the poststroke brain is both temporally and spatially coordinated [8,25,27,28]. With an early rise of resident microglia after stroke, peripheral immune cells, including monocytes/macrophages, myeloid dendritic cells, and neutrophils, appear in the brain within 1 day poststroke, peak in number at 3 days poststroke, and remain sustained until 7 days poststroke.…”

Section: Impact Of Stroke On Immunitymentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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“…Microglia exert neurotoxic functions through the production of ROS via NADPH oxidase, proinflammatory cytokines, and matrix metalloproteinase‐9. These events precede leukocyte infiltration into the brain and may play a pivotal role in mediating the initial increase in blood‐brain barrier (BBB) permeability and the early infiltration of circulating leukocytes into the brain (Jin et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

Umekawa

Osman

Han

et al. 2015

Glia

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The mechanisms of neuronal injury after hypoxia–ischemia (HI) are different in the immature and the adult brain, but microglia activation has not been compared. The purpose of this study was to phenotype resident microglia and blood‐derived macrophages in the hippocampus after HI in neonatal (postnatal day 9, P9) or adult (3 months of age, 3mo) mice. Unilateral brain injury after HI was induced in Cx3cr1GFP/+Ccr2RFP/+ male mice on P9 (n = 34) or at 3mo (n = 53) using the Vannucci model. Resident microglia (Cx3cr1‐GFP+) proliferated and were activated earlier after HI in the P9 (1–3 days) than that in the 3mo hippocampus, but remained longer in the adult brain (3–7 days). Blood‐derived macrophages (Ccr2‐RFP+) peaked 3 days after HI in both immature (P9) and adult (3mo) hippocampi but were twice as frequent in adult brains, 41% vs. 21% of all microglia/macrophages. CCL2 expression was three times higher in the P9 hippocampi, indicating that the proinflammatory response was more pronounced in the immature brain after HI. This corresponded well with the higher numbers of galectin‐3‐positive resident microglia in the P9 hippocampi, but did not correlate with CD16/32‐ or CD206‐positive resident microglia or blood‐derived macrophages. In conclusion, resident microglia, rather than infiltrating blood‐derived macrophages, proliferate and are activated earlier in the immature than in the adult brain, but remain increased longer in the adult brain. The inflammatory response is more pronounced in the immature brain, and this correlate well with galectin‐3 expression in resident microglia. GLIA 2015;63:2220–2230

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Inflammatory mechanisms in ischemic stroke: role of inflammatory cells

Cited by 1,339 publications

References 117 publications

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Microglia and Monocyte-Derived Macrophages in Stroke

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

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