Ischemic Preconditioning in White Matter: Magnitude and Mechanism

Hamner, Margaret A.; Ye, Zucheng; Lee, Richard V.; Colman, Jamie R.; Le, Thu H.; Gong, Davin C.; Ransom, Bruce R.; Weinstein, Jonathan R.

doi:10.1523/jneurosci.2544-15.2015

Cited by 40 publications

(80 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both IPC and TLR agonist-induced cross-tolerance are attenuated in mice with deficiencies in IFN signaling [13]. We provide evidence here that IPC results in marked changes in the innate immune cell population in cortex ( [11]. These findings have provided strong evidence to support a key role for innate immune signaling and microglia in preconditioning-mediated neuroprotection.…”

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 57%

“…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.…”

Section: Preconditioningmentioning

confidence: 99%

“…Regulates metabolic genes to protect against hypoxia Multiple CNS cells [17,22], peripheral immune cells [23] Type 1 IFNs Regulate neuroimmune function Microglia [11], peripheral macrophages [24,25] Refractive microRNAs Modulate gene expression post-translationally Multiple CNS cells [18,26] Polycomb group proteins Induce lasting alterations of gene-transcription programs…”

Section: Hif-1mentioning

confidence: 99%

“…Mxultiple CNS cells [18,26] histone modulators TNF-α Neuroprotectant and/or proapoptotic Astrocytes [19][20][21], microglia [19][20][21], peripheral immune cells [19][20][21] Neuroprotective IRFs Downstream mediators of the reprogrammed genomic response to ischemia Microglia [11], macrophages [11] TLRs Reprograms cellular genomic response to ischemia Circulating leukocytes [16], endothelial cells [16], microglia [17,18] TGF-β Promotes repair of neurovascular unit, regulates immune system function Astrocytes [20,27], microglia [27], T cells [28] TLR = Toll-like receptor; TNF = tumor necrosis factor; NFkB = nuclear factor kB; CNS = central nervous system; HIF = hypoxia-inducible factor; IFN = interferon; IRF = IFN regulatory factor; TGF = transforming growth factor geared at less invasive methods of inducing preconditioning. These include the administration of therapeutics, such as cytokines or TLR agonists which play a role in preconditioning, or the concept of remote IPC (RIPC), which uses remote limb ischemia to induce neuroprotection equivalent to direct preconditioning of the brain using models of focal ischemia [4,30,31].…”

Section: Hif-1mentioning

confidence: 99%

“…-/-mice [11,12], and agonists of multiple other TLRs also induce c r o s s -t o l e r a n c e [ 4 5 -4 7 ] . G e n o m i c s t u d i e s o n preconditioned cortical tissue have identified robust expression of IFN-stimulated genes (ISGs) [5,13]-a well-defined innate immune response activated by type 1 IFNs such as IFN-α and IFN-β.…”

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

See 4 more Smart Citations

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

Self Cite

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 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.

show abstract

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 57%

Section: Preconditioningmentioning

confidence: 99%

Section: Hif-1mentioning

confidence: 99%

Section: Hif-1mentioning

confidence: 99%

Section: Molecular Mediators Of Preconditioningmentioning

confidence: 99%

See 3 more Smart Citations

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

Type‐1 interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson's disease

Main

Zhang

Brody

et al. 2016

Glia

View full text Add to dashboard Cite

Type-1 interferons (IFNs) are pleiotropic cytokines with a critical role in the initiation and regulation of the pro-inflammatory response. However, the contribution of the type-1 IFNs to CNS disorders, specifically chronic neuropathologies such as Parkinson's disease is still unknown. Here, we report increased type-1 IFN signaling in both post mortem human Parkinson's disease samples and in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model. In response to MPTP, mice lacking the type-1 IFN receptor (IFNAR1(-/-) ) displayed decreased type-1 IFN signaling, an attenuated pro-inflammatory response and reduced loss of dopaminergic neurons. The neuroprotective potential of targeting the type-1 IFN pathway was confirmed by reduced neuroinflammation and DA cell death in mice treated with a blocking monoclonal IFNAR1 (MAR-1) antibody. The MPTP/MAR-1 treated mice also displayed increased striatal dopamine levels and improved behavioural outcomes compared to their MPTP/IgG controls. These data, implicate for the first time, a deleterious role for the type-1 IFNs as key modulators of the early neuroinflammatory response and therefore the neuronal cell death in Parkinson's disease. GLIA 2016;64:1590-1604.

show abstract

The role of microglia in ischemic preconditioning

McDonough

Weinstein

2019

Glia

View full text Add to dashboard Cite

Ischemic preconditioning (IPC) is an experimental phenomenon in which a brief ischemic stimulus confers protection against a subsequent prolonged ischemic event. Initially thought to be due to mechanistic changes in neurons, our understanding of IPC has evolved to encompass a global reprogramming of the Central Nervous System (CNS) after transient ischemia/reperfusion that requires innate immune signaling pathways including Toll‐like receptors (TLRs) and Type I interferons. Microglia are the CNS resident neuroimmune cells that express these key innate immune receptors. Studies suggest that microglia are required for IPC‐mediated neuronal and axonal protection. Multiple paradigms targeting TLRs have converged on a distinctive Type I interferon response in microglia that is critical for preconditioning‐mediated protection against ischemia. These pathways can be targeted through administration of TLR agonists, cytokines including interferon‐β, and pharmaceutical agents that induce preconditioning through cross‐tolerance mechanisms. Transcriptomic analyses and single cell RNA studies point to specific gene expression signatures in microglia that functionally shift these mutable cells to an immunomodulatory or protective phenotype. Although there are technological challenges and gaps in knowledge to overcome, the targeting of specific molecular signaling pathways in microglia is a promising direction for development of novel and effective pharmacotherapies for stroke. Studies on preconditioning in animal models, including nonhuman primates, show promise as prophylactic preconditioning treatments for selected at risk patient populations. In addition, our growing understanding of the mechanisms of IPC‐mediated protection is identifying novel cellular and molecular targets for therapeutic interventions that could apply broadly to both acute stroke and chronic vascular cognitive impairment patients.

show abstract

Ischemic Preconditioning in White Matter: Magnitude and Mechanism

Cited by 40 publications

References 65 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Type‐1 interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson's disease

The role of microglia in ischemic preconditioning

Contact Info

Product

Resources

About