Central nervous system injury-induced immune deficiency syndrome

Meisel, Christian; Schwab, Jan M.; Prass, Konstantin; Meisel, Andreas; Dirnagl, Ulrich

doi:10.1038/nrn1765

Cited by 813 publications

(754 citation statements)

References 133 publications

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“…Another attractive feature of using Kv1.3 inhibitors to reduce neuroinflammation in the wake of ischemic stroke is that Kv1.3 inhibitors are known to be immunomodulators rather than immunosuppressants and do not impair the ability of rodents to clear acute infections or of primates to develop vaccine responses 5, 8. Kv1.3 inhibitors are therefore unlikely to further increase the risk of respiratory and urinary tract infections, which are responsible for considerable morbidity and mortality after stroke 45, 49. This phenomenon, which manifests as lymphopenia in stroke patients and rodent models, is mediated by an increased release of cortisol and catecholamines,49 which has recently been shown to induce a higher bone marrow output of inflammatory monocytes and neutrophils and a drastic reduction in lymphoid progenitors 50.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…This early immune activation often progresses to immune suppression in patients with stroke. Some studies have suggested that lymphopenia and immunosuppression occur as a compensatory mechanism against brain damage by attenuating autoreactive T-cell targeting of CNS self-antigens [14,15]. Other studies have demonstrated that stroke-induced immune suppression increases the risk of secondary infections and increases mortality rates in patients [16,17].…”

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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“…The signals and mechanisms that trigger the SNS and the HPA to induce stroke-induced immunodepression remain unclear. One cause appears to be the increased pro-inflammatory cytokine production that occurs early after stroke and central nervous system (CNS) injury-specific neurogenic signaling (for review see Dirnagl et al, 2007;Meisel et al, 2005). An early study by Prass et al (2003) blocked the SNS and HPA by administration of a b-adrenoceptor antagonist (propranolol) and a glucocorticoid receptor inhibitor (RU486), respectively.…”

Section: Stroke-induced Immunodeficiency Syndromementioning

confidence: 99%

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

Brait

Arumugam

Drummond

et al. 2012

J Cereb Blood Flow Metab

185

129

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Following an ischemic stroke, T lymphocytes become activated, infiltrate the brain, and appear to release cytokines and reactive oxygen species to contribute to early inflammation and brain injury. However, some subsets of T lymphocytes may be beneficial even in the early stages after a stroke, and recent evidence suggests that T lymphocytes can also contribute to the repair and regeneration of the brain at later stages. In the hours to days after stroke, T-lymphocyte numbers are then reduced in the blood and in secondary lymphoid organs as part of a 'stroke-induced immunodeficiency syndrome,' which is mediated by hyperactivity of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, resulting in increased risk of infectious complications. Whether or not poststroke T-lymphocyte activation occurs via an antigenindependent process, as opposed to a classical antigen-dependent process, is still controversial. Although considerable recent progress has been made, a better understanding of the roles of the different T-lymphocyte subpopulations and their temporal profile of damage versus repair will help to clarify whether T-lymphocyte targeting may be a viable poststroke therapy for clinical use.

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Central nervous system injury-induced immune deficiency syndrome

Cited by 813 publications

References 133 publications

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

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

Microglia and Monocyte-Derived Macrophages in Stroke

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

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