Stroke and the immune system: from pathophysiology to new therapeutic strategies

Macrez, Richard; Ali, Carine; Toutirais, Olivier; Mauff, Brigitte Le; Defer, Gilles; Dirnagl, Ulrich; Vivien, Denis

doi:10.1016/s1474-4422(11)70066-7

Cited by 459 publications

(372 citation statements)

References 129 publications

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“…Furthermore, when activated by oxygenglucose-deprived (OGD) neurons, microglia release TNF-α [70]. Responding peripheral immune cells also release TNF-α in response to ischemia [19,71]. TNF-α is required for cross-tolerance induced by multiple TLR agonists [72,73].…”

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of proand anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

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Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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“…However, some potential targets in the immune system have not been fully characterized (37). Many defined targets have been described that show promise (7,(36)(37)(38)(39)(40)(41)(42). Cryab is notable because it is endogenously produced after stroke, and has known antiinflammatory effects on inflammatory immune responses (11).…”

Section: Discussionmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

128

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Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab −/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

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“…Using cultured neonatal mouse microglia, our group recently demonstrated that Kv1.3 expression increases following stimulation with the M1‐polarizing stimuli LPS or LPS plus IFN‐ γ , while IL‐4 stimulation induced a down‐regulation of Kv1.3 and an increase in currents for the inward‐rectifier K + channel Kir2.1,19 suggesting that Kv1.3 blockers might be able to preferentially target detrimental proinflammatory M1 microglia functions. We therefore hypothesized that Kv1.3 blockers could be useful for ameliorating pathology in ischemic stroke, where activated microglia significantly contribute to the secondary expansion of the infarct 20, 21. In order to test this therapeutic hypothesis, we here confirmed Kv1.3 expression on microglia in infarcted rodent and human brain and then evaluated our small molecule blocker PAP‐122 first in organotypic brain slices and then in middle cerebral artery occlusion (MCAO) with reperfusion.…”

Section: Introductionmentioning

confidence: 90%

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Chen

Nguyen

Maezawa

et al. 2017

Ann Clin Transl Neurol

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ObjectiveInhibitors of the voltage‐gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up‐regulated on “M1‐like” microglia, we here tested the therapeutic hypothesis that the brain‐penetrant small‐molecule Kv1.3‐inhibitor PAP‐1 reduces secondary inflammatory damage after ischemia/reperfusion.MethodsWe studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP‐1 in hypoxia‐exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP‐1 administration was started 12 h after reperfusion.ResultsWe observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP‐1 reduced microglia activation and increased neuronal survival in hypoxia‐exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP‐1 dose‐dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL‐1β and IFN‐γ without affecting IL‐10 and brain‐derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species.InterpretationOur findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting “M1‐like” inflammatory microglia/macrophage functions in ischemic stroke.

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Stroke and the immune system: from pathophysiology to new therapeutic strategies

Cited by 459 publications

References 129 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

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