The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity

Li, Yan; Zhu, Ziyu; Huang, Tingting; Zhou, Yue; Wang, Xin; Yang, Liqun; Chen, Zeng‐Ai; Yu, Weifeng; Li, Peiying

doi:10.1111/cns.13081

Cited by 66 publications

(62 citation statements)

References 218 publications

(241 reference statements)

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“…The role of PVMs in BBB permeability is complicated. It is possible that PVMs facilitate BBB integrity under physiological conditions, while participate in BBB disruption under diseased status . Some evidence is discussed under Section 2.1 in this regard.…”

Section: Pvm Alterations In Diseased Brainmentioning

confidence: 99%

Brain perivascular macrophages: Recent advances and implications in health and diseases

2019

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Brain perivascular macrophages (PVMs) belong to a distinct population of brain‐resident myeloid cells located within the perivascular space surrounding arterioles and venules. Their characterization depends on the combination of anatomical localization, phagocytic capacity, and molecular markers. Under physiological status, they provide structural and functional support for maintaining brain homeostasis, including facilitation of blood‐brain barrier integrity and lymphatic drainage, and exertion of immune functions such as phagocytosis and antigen presentation. Increasing evidence also implicates their specific roles in diseased brain, ranging from cerebrovascular diseases, Aβ pathologies, infections, and autoimmunity. Collectively, PVMs are key components of the brain‐resident immune system, actively participate in a broad‐spectrum of processes in normal and diseased status. Details of the processes are largely underexplored. Targeting PVMs would lead to new insights and be a promising strategy for a broad array of human diseases.

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Section: Pvm Alterations In Diseased Brainmentioning

confidence: 99%

Brain perivascular macrophages: Recent advances and implications in health and diseases

2019

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“…It has been suggested that RSG, a PPAR‐γ agonist, can drive microglial/macrophage polarization and phenotypic change, which is highly dynamic after ischemic injury . We next examined whether RSG treatment altered the function and phenotypic change of microglia/macrophage in the tPA‐treated stroke mice.…”

Section: Resultsmentioning

confidence: 99%

“…It is emerging that the PPAR‐γ is constitutively expressed in microglia and activating PPAR‐γ in microglia may regulate the phenotypic change of microglia . PPAR‐γ activation could favor a reprogramming process of microglia toward a beneficial phenotype, with anti‐inflammatory and tissue‐repair properties . Interestingly, previous studies have shown that 1 day after ischemia, the microglia/macrophages adopt an anti‐inflammatory phenotype that progressively evolves toward a neurotoxic phenotype at day 7 poststroke .…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, the administration of tPA may increase the risk of hemorrhagic transformation(HT), especially when delayed beyond 4.5 hours after the onset of ischemia, leading to poor clinical outcomes in stroke patients . Accumulating evidence suggests that HT is associated with disruption of blood‐brain barrier (BBB), which may occur early after stroke and largely limit the clinical use of tPA thrombolysis for stroke patients . Thus, there is an unmet need for developing an adjuvant agent that could protect the BBB integrity and extend the therapeutic window of tPA to benefit more stroke patients for safe thrombolysis and better functional recovery …”

Section: Introductionmentioning

confidence: 99%

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Rosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke

Zhu

et al. 2019

CNS Neurosci Ther

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Objective Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood‐brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti‐inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA‐induced HT after stroke. Methods and results We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA‐induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA‐treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA‐treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA‐alone‐treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down‐regulated in microglia of the RSG‐treated mice. We further found that the expression of Arg‐1 was also upregulated in those tPA and RSG‐treated stroke mice and the protection against tPA‐induced HT and BBB disruption in these mice were abolished in the presence of PPAR‐γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). Conclusions RSG treatment protects against BBB damage and ameliorates HT in delayed tPA‐treated stroke mice by activating PPAR‐γ and favoring microglial polarization toward anti‐inflammatory phenotype.

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“…Whether this direct interaction is time‐dependent warrants further investigation. Manipulating CNS‐periphery crosstalk to impair proinflammatory N1 neutrophils and amplify the effect of N2 neutrophils may be a feasible treatment approach for stroke …”

Section: Microglia‐neighboring Cells Crosstalk and Interventions For mentioning

confidence: 99%

Potential microglia‐based interventions for stroke

Huang

Yang

et al. 2020

CNS Neurosci Ther

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A large number of families worldwide suffer from the physical and mental burden posed by stroke. An increasing number of studies aimed at the prevention and treatment of stroke have been conducted. Specifically, manipulating the immune response to stroke is under intense investigation. Microglia are the principal immune cells in the brain and are the first line of defense against the pathophysiology induced by stroke. Increasing evidence has suggested that microglia play diverse roles that depend on dynamic interactions with neurons, astrocytes, and other neighboring cells both in the normal brain and under pathological conditions, including stroke. Moreover, there are dynamic alterations in microglial functions with respect to aging and sex differences in the human brain, which offer a deep understanding of the conditions of stroke patients of different ages and sex. Hence, we review the dynamic microglial reactions caused by aging, sex, and crosstalk with neighboring cells both in normal conditions and after stroke and relevant potential interventions.

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The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity

Cited by 66 publications

References 218 publications

Brain perivascular macrophages: Recent advances and implications in health and diseases

Brain perivascular macrophages: Recent advances and implications in health and diseases

Rosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke

Potential microglia‐based interventions for stroke

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