Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

Khorooshi, Reza; Mørch, Marlene; Holm, Thomas Hellesøe; Berg, Carsten Tue; Dieu, Ruthe; Dræby, Dina; Issazadeh‐Navikas, Shohreh; Weiß, Siegfried; Owens, Trevor

doi:10.1007/s00401-015-1418-z

“…The pioneering papers in the RIPC field suggest that neuroprotection is induced rapidly [30,31,37]; however, the duration of protection has not been determined [37,38]. Molecular determinants behind the phenomenon of RIPC have not been fully elucidated, but there is some evidence of overlap with molecular mediators of ischemic and LPS preconditioning, including hypoxiainducible factor (HIF)-1α [39], and inflammatory factors [40][41][42][43]. Remote limb ischemia may induce global expression of these molecular mediators of preconditioning that confers protection to multiple organ systems, including the brain.…”

Section: Hif-1mentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

¹

,

Weinstein

²

2016

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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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“…In this study, myeloid cells in the meninges and choroid plexus, parenchymal microglia, and CD45 high leukocytes produced type I IFNs in response to poly I:C exposure, and consequently microglia and astrocytes up-regulated the ISG products IRF7, IRF9, and CXCL10 [68]. Interestingly, microglia expressed higher levels of IRF7 than astrocytes [68], suggesting a greater response and engagement of the interferon signaling machinery in microglia. Our results showing a synergistic effect of TLR3/TLR4 on type I IFN production (Fig.…”

Section: Type I Interferon Signaling In Microglia Modulates Neuroimmumentioning

confidence: 95%

“…The timing of these effects suggests that IFNβ is an early response to neuroinflammation, with the data from the IFNAR1 deficient animals implying that it is neuroprotective and may delay onset of symptoms. The contribution of IFNβ facilitates a transition from a pro-inflammatory to a regulatory immune environment, thus ameliorating symptoms of MS. Additional mouse studies on the suppressive effect that administration of the TLR3 agonist poly I:C has on EAE suggest that this effect is mediated by induction of type I IFNs [68]. In this study, myeloid cells in the meninges and choroid plexus, parenchymal microglia, and CD45 high leukocytes produced type I IFNs in response to poly I:C exposure, and consequently microglia and astrocytes up-regulated the ISG products IRF7, IRF9, and CXCL10 [68].…”

Section: Type I Interferon Signaling In Microglia Modulates Neuroimmumentioning

confidence: 99%

“…The contribution of IFNβ facilitates a transition from a pro-inflammatory to a regulatory immune environment, thus ameliorating symptoms of MS. Additional mouse studies on the suppressive effect that administration of the TLR3 agonist poly I:C has on EAE suggest that this effect is mediated by induction of type I IFNs [68]. In this study, myeloid cells in the meninges and choroid plexus, parenchymal microglia, and CD45 high leukocytes produced type I IFNs in response to poly I:C exposure, and consequently microglia and astrocytes up-regulated the ISG products IRF7, IRF9, and CXCL10 [68]. Interestingly, microglia expressed higher levels of IRF7 than astrocytes [68], suggesting a greater response and engagement of the interferon signaling machinery in microglia.…”

Section: Type I Interferon Signaling In Microglia Modulates Neuroimmumentioning

confidence: 99%

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Microglial Interferon Signaling and White Matter

McDonough

¹

,

Lee

²

,

Weinstein

³

2017

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Microglia, the resident immune cells of the CNS, are primary regulators of the neuroimmune response to injury. Type I interferons (IFNs), including the IFNαs and IFNβ, are key cytokines in the innate immune system. Their activity is implicated in the regulation of microglial function both during development and in response to neuroinflammation, ischemia, and neurodegeneration. Data from numerous studies in multiple sclerosis (MS) and stroke suggest that type I IFNs can modulate the microglial phenotype, influence the overall neuroimmune milieu, regulate phagocytosis, and affect blood–brain barrier integrity. All of these IFN-induced effects result in numerous downstream consequences on white matter pathology and microglial reactivity. Dysregulation of IFN signaling in mouse models with genetic deficiency in ubiquitin specific protease 18 (USP18) leads to a severe neurological phenotype and neuropathological changes that include white matter microgliosis and pro-inflammatory gene expression in dystrophic microglia. A class of genetic disorders in humans, referred to as pseudo-TORCH syndrome (PTS) for the clinical resemblance to infection-induced TORCH syndrome, also show dysregulation of IFN signaling, which leads to severe neurological developmental disease. In these disorders, the excessive activation of IFN signaling during CNS development results in a destructive interferonopathy with similar induction of microglial dysfunction as seen in USP18 deficient mice. Other recent studies implicate “microgliopathies” more broadly in neurological disorders including Alzheimer’s disease (AD) and MS, suggesting that microglia are a potential therapeutic target for disease prevention and/or treatment, with interferon signaling playing a key role in regulating the microglial phenotype.

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“…However, the full extent and mechanisms of IFN signaling in IPCmediated protection remain to be explored. The cellular source of IFN-β in the postischemic brain is unknown, but there are several possible sources such as peripheral macrophages [53,54] and astrocytes [55][56][57][58]. Published studies also suggest neurons [59] are capable of releasing IFN-β under specific conditions.…”

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

Correction to: Neuroimmune Response in Ischemic Preconditioning

McDonough

¹

,

Weinstein

²

2018

View full text Add to dashboard Cite

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 Tolllike receptors and type 1 interferons. Brain ischemia results in release of pro-and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammatory 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. Keywords PreconditioningIschemic preconditioning (IPC) is an experimental phenomenon in which a brief period of ischemia confers robust neuroprotection against subsequent ischemic events [1-3]. It is important to note that preconditioning does not reduce the incidence of stroke, but rather ameliorates the pathophysiologic response to cerebral ischemia and results in a smaller infarct volume and improved poststroke recovery [4][5][6]. Clinical studies suggest that patients with stroke who suffered a recent prior transient ischemic attack have better outcomes than those who did not, implying that a human correlate to experimental IPC exists [7,8]. Elucidating the mechanisms of IPC is considered a critical challenge in stroke research [9,10]. Recent literature has implicated innate immune pathways, including Toll-like receptors (TLRs) [11,12] and type 1 interferon (IFN) signaling [5,11,13] in IPC-mediated protection.Due to a technical error in the production process, the earlier version of this article contained numerous errors in the reference numbering. We are reprinting the entire article in the correction for readabilityThe online version of the original article can be found at https://doi

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Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

Cited by 63 publications

References 42 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Microglial Interferon Signaling and White Matter

Correction to: Neuroimmune Response in Ischemic Preconditioning

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