In vivo inhibition of miR-155 significantly alters post-stroke inflammatory response

Peña-Philippides, Juan Carlos; Caballero-Garrido, Ernesto; Lordkipanidze, Tamar; Roitbak, Tamara

doi:10.1186/s12974-016-0753-x

Cited by 92 publications

(74 citation statements)

References 72 publications

(91 reference statements)

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“…We, therefore, assessed the NO release in all HBMEC experimental groups, but found no significant differences at 48 hours after the oligonucleotide transfections (Figure 3B). As a major inflammatory miRNA, miR‐155 regulates cytokine expression, which could significantly influence the endothelial TJs 19. It is also known, that OGD triggers the endothelial cell activation leading to increased cytokine release.…”

Section: Resultsmentioning

confidence: 99%

“…Improved TJ integrity in the inhibitor‐injected animals was accompanied by increased levels of the TJ protein ZO‐1 in brain tissue extracts 18. In addition, we proposed that miR‐155 inhibition–induced stabilization of TJs could be associated with altered poststroke inflammatory response 19. Our in vivo studies involving systemic anti–miR‐155 injections did not precisely determine whether miR‐155 inhibition directly influenced the vascular endothelium.…”

Section: Introductionmentioning

confidence: 87%

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Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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BackgroundBrain microvascular endothelial cells form a highly selective blood brain barrier regulated by the endothelial tight junctions. Cerebral ischemia selectively targets tight junction protein complexes, which leads to significant damage to cerebral microvasculature. Short noncoding molecules called microRNAs are implicated in the regulation of various pathological states, including endothelial barrier dysfunction. In the present study, we investigated the influence of microRNA‐155 (miR‐155) on the barrier characteristics of human primary brain microvascular endothelial cells (HBMECs).Methods and ResultsOxygen‐glucose deprivation was used as an in vitro model of ischemic stroke. HBMECs were subjected to 3 hours of oxygen‐glucose deprivation, followed by transfections with miR‐155 inhibitor, mimic, or appropriate control oligonucleotides. Intact normoxia control HBMECs and 4 oxygen‐glucose deprivation–treated groups of cells transfected with appropriate nucleotide were subjected to endothelial monolayer electrical resistance and permeability assays, cell viability assay, assessment of NO and human cytokine/chemokine release, immunofluorescence microscopy, Western blot, and polymerase chain reaction analyses. Assessment of endothelial resistance and permeability demonstrated that miR‐155 inhibition improved HBMECs monolayer integrity. In addition, miR‐155 inhibition significantly increased the levels of major tight junction proteins claudin‐1 and zonula occludens protein‐1, while its overexpression reduced these levels. Immunoprecipitation and colocalization analyses detected that miR‐155 inhibition supported the association between zonula occludens protein‐1 and claudin‐1 and their stabilization at the HBMEC membrane. Luciferase reporter assay verified that claudin‐1 is directly targeted by miR‐155.ConclusionsBased on these results, we conclude that miR‐155 inhibition–induced strengthening of endothelial tight junctions after oxygen‐glucose deprivation is mediated via its direct target protein claudin‐1.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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“…In the adult stroke model, the expression of miR-155 is significantly affected. Inhibition of miR-155 reduces the ischemic inflammatory responses, which contributes to the reduced brain tissue damage and promotes brain repair and functional recovery (Caballero-Garrido et al , 2015; Pena-Philippides et al , 2016). …”

Section: Mirna Modulation In Neuroinflammationmentioning

confidence: 99%

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Concepcion

Meng

et al. 2017

Progress in Neurobiology

185

189

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Perinatal hypoxia-ischemia remains the primary cause of acute neonatal brain injury, leading to a high mortality rate and long-term neurological deficits, such as behavioral, social, attentional, cognitive and functional motor deficits. An ever-increasing body of evidence shows that the immune response to acute cerebral hypoxia-ischemia is a major contributor to the pathophysiology of neonatal brain injury. Hypoxia-ischemia provokes an intravascular inflammatory cascade that is further augmented by the activation of resident immune cells and the cerebral infiltration of peripheral immune cells response to cellular damages in the brain parenchyma. This prolonged and/or inappropriate neuroinflammation leads to secondary brain tissue injury. Yet, the long-term effects of immune activation, especially the adaptive immune response, on the hypoxic-ischemic brain still remain unclear. The focus of this review is to summarize recent advances in the understanding of post-hypoxic-ischemic neuroinflammation triggered by the innate and adaptive immune responses and to discuss how these mechanisms modulate the brain vulnerability to injury. A greater understanding of the reciprocal interactions between the hypoxic-ischemic brain and the immune system will open new avenues for potential immunomodulatory therapy in the treatment of neonatal brain injury.

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“…Tail vein injection of a specific anti-miR-155 inhibitor was reported to promote functional recovery in a mouse model of stroke when carried out 48 h later (Caballero- Garrido et al, 2015; Pena-Philippides et al, 2016). This action was associated with improved blood flow, reduced infarct size and edema, attenuated neuronal damage and inflammatory cytokine/chemokine presence, and preserved microvascular integrity in the peri-infarct area.…”

Section: Recently Identified Molecular/cellular Targets and Approachesmentioning

confidence: 99%

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Shekhar

Cunningham

Pabbidi

et al. 2018

European Journal of Pharmacology

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Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.

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In vivo inhibition of miR-155 significantly alters post-stroke inflammatory response

Cited by 92 publications

References 72 publications

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

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