MicroRNAs in Neuroinflammation: Implications in Disease Pathogenesis, Biomarker Discovery and Therapeutic Applications.
TL;DR: The aim of this review is to summarize the mode of regulation for several important and well-studied microRNAs in the context of neuroinflammation, includingmiR-155, miR-146a, miM-124,MiR-21 and let-7, and the pathological consequences of miRNA deregulation during disorders that feature neuro inflammation are discussed.
Abstract: The central nervous system can respond to threat via the induction of an inflammatory response. Under normal circumstances this response is tightly controlled, however uncontrolled neuroinflammation is a hallmark of many neurological disorders. MicroRNAs are small non-coding RNA molecules that are important for regulating many cellular processes. The ability of microRNAs to modulate inflammatory signaling is an area of ongoing research, which has gained much attention in recent years. MicroRNAs may either promote or restrict inflammatory signaling, and either exacerbate or ameliorate the pathological consequences of excessive neuroinflammation. The aim of this review is to summarize the mode of regulation for several important and well-studied microRNAs in the context of neuroinflammation, including miR-155, miR-146a, miR-124, miR-21 and let-7. Furthermore, the pathological consequences of miRNA deregulation during disorders that feature neuroinflammation are discussed, including Multiple Sclerosis, Alzheimer’s disease, Parkinson’s disease, Prion diseases, Japanese encephalitis, Herpes encephalitis, ischemic stroke and traumatic brain injury. There has also been considerable interest in the use of altered microRNA signatures as biomarkers for these disorders. The ability to modulate microRNA expression may even serve as the basis for future therapeutic strategies to help treat pathological neuroinflammation.
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TL;DR: In this paper, the authors present a review of Japanese encephalitis (JE) in Asia, focusing on rural and suburban areas where rice culture and pig farming coexist.
Abstract: Introduction Japanese encephalitis (JE) is among the most important viral encephalitides in Asia, especially in rural and suburban areas where rice culture and pig farming coexist. (1-3) It has also occurred rarely and sporadically in northern Australia and parts of the Western Pacific. (4-6) JE is due to infection with the JE virus (JEV), a mosquito-borne flavivirus. The main JEV transmission cycle involves Culex tritaeniorhynchus mosquitoes and similar species that lay eggs in rice paddies and other open water sources, with pigs and aquatic birds as principal vertebrate amplifying hosts. (1,2,7) Humans are generally thought to be dead-end JEV hosts, i.e. they seldom develop enough viremia to infect feeding mosquitoes. Fewer than 1% of human JEV infections result in JE. Approximately 20-30% of JE cases are fatal and 30-50% of survivors have significant neurologic sequelae. (8) JE is primarily a disease of children and most adults in endemic countries have natural immunity after childhood infection, but all age groups are affected. In most temperate areas of Asia, JEV is transmitted mainly during the warm season, when large epidemics can occur. In the tropics and subtropics, transmission can occur year-round but often intensifes during the rainy season. (1-3) The global incidence of JE is unknown because the intensity and quality of JE surveillance and the availability of diagnostic laboratory testing vary throughout the world. Countries that have implemented high-quality childhood JE vaccination programmes have seen a dramatic decline in JE incidence. Although JE is reportable to the World Health Organization (WHO) by its Member States, reporting is highly variable and incomplete. In the late 1980s, Burke and Leake estimated that 50 000 new cases of JE occurred annually among the 2.4 billion people living in the 16 Asian countries considered endemic at the time (approximate overall annual incidence: 2 per 100 000). (2) In the intervening two decades, despite major population growth, urbanization, changes in agricultural practices and increased use of the JE vaccine in many countries, this figure has been widely quoted, including very recently. (9-13) In 2000, assuming an annual, age-group-specific incidence of 25 cases per 100 000, Tsai estimated that in the absence of vaccination 175 000 cases of JE would occur annually among Asian children aged 0-14 years living in rural areas. (14) The current study used more recent, published, local or national incidence estimates and current population data to produce an updated estimate of the annual global incidence of JE. Methods We approximated the JE-affected territory of each of the 24 countries endemic for JE using a recent update (15) of an earlier approximation by Tsai (16) with some modifications (Table 1, available at: http://www.who.int/bulletin/ volumes/89/10/10-085233). Based on these same approximations, (15,16) we then stratified the JE-affected territory of some countries (e.g. China excluding Taiwan, India and Nepal) into two or more incidence strata. Because suitable studies of JE incidence were not available for every endemic country or incidence stratum, we sorted JE-endemic countries and incidence strata into 10 incidence groups (A, B, C1, C2 and D through I) based primarily on geographic proximity, ecologic similarity, vaccine programme similarity. Table 1 briefly describes the status of each endemic country's JE vaccination programme as of 2009, according to recent publications and unpublished sources. (8,17-20) Incidence data We identified studies that contained potentially useful data on the incidence of JE in Asia in a manner similar to the one used in a recent study of global typhoid fever incidence. (21) Whenever possible, this review followed the relevant guidelines for Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). (22) The review process is described as follows and no protocol is available. …
539 citations
TL;DR: The different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery are addressed.
Abstract: The blood-brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1-3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.
150 citations
TL;DR: The role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer's (AD), Parkinson's (PD), Huntington’s (HD) disease, and amyotrophic lateral sclerosis (ALS) are reviewed.
Abstract: MicroRNAs are post-transcriptional regulators of gene expression, crucial for neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases neuronal vulnerability to cellular stress and may contribute to the development and progression of neurodegenerative diseases. All major neurodegenerative disorders are also associated with oxidative stress, which is widely recognized as a potential target for protective therapies. Albeit often considered separately, microRNA networks and oxidative stress are inextricably entwined in neurodegenerative processes. Oxidative stress affects expression levels of multiple microRNAs and, conversely, microRNAs regulate many genes involved in an oxidative stress response. Both oxidative stress and microRNA regulatory networks also influence other processes linked to neurodegeneration, such as mitochondrial dysfunction, deregulation of proteostasis, and increased neuroinflammation, which ultimately lead to neuronal death. Modulating the levels of a relatively small number of microRNAs may therefore alleviate pathological oxidative damage and have neuroprotective activity. Here, we review the role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD) disease, and amyotrophic lateral sclerosis (ALS). We also discuss the problems associated with the use of oversimplified cellular models and highlight perspectives of studying microRNA regulation and oxidative stress in human stem cell-derived neurons.
111 citations
TL;DR: Investigations of signatures of miRNAs and proteins and the biological activity of EVs, isolated from hiPSC-NSCs through a combination of anion-exchange chromatography and size-exclusion chromatography revealed that EVs were enriched with miRN as well as proteins involved in neuroprotective, anti-apoptotic, antioxidant,anti-inflammatory, blood-brain barrier repairing, neurogenic and Aβ reducing activities.
Abstract: Grafting of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise for brain repair after injury or disease, but safety issues have hindered their clinical application. Employing nano-sized extracellular vesicles (EVs) derived from hiPSC-NSCs appears to be a safer alternative because they likely have similar neuroreparative properties as NSCs and are amenable for non-invasive administration as an autologous or allogeneic off-the-shelf product. However, reliable methods for isolation, characterization and testing the biological properties of EVs are critically needed for translation. We investigated signatures of miRNAs and proteins and the biological activity of EVs, isolated from hiPSC-NSCs through a combination of anion-exchange chromatography (AEC) and size-exclusion chromatography (SEC). AEC and SEC facilitated the isolation of EVs with intact ultrastructure and expressing CD9, CD63, CD81, ALIX and TSG 101. Small RNA sequencing, proteomic analysis, pathway analysis and validation of select miRNAs and proteins revealed that EVs were enriched with miRNAs and proteins involved in neuroprotective, anti-apoptotic, antioxidant, anti-inflammatory, blood-brain barrier repairing, neurogenic and Aβ reducing activities. Besides, EVs comprised miRNAs and/or proteins capable of promoting synaptogenesis, synaptic plasticity and better cognitive function. Investigations using an in vitro macrophage assay and a mouse model of status epilepticus confirmed the anti-inflammatory activity of EVs. Furthermore, the intranasal administration of EVs resulted in the incorporation of EVs by neurons, microglia and astrocytes in virtually all adult rat and mouse brain regions, and enhancement of hippocampal neurogenesis. Thus, biologically active EVs containing miRNAs and proteins relevant to brain repair could be isolated from hiPSC-NSC cultures, making them a suitable biologic for treating neurodegenerative disorders.
78 citations
TL;DR: It is found that acupuncture notably repressed the expression of inflammatory cytokines in the hippocampus and plasma of VD rats, providing evidence that acupuncture attenuates cognitive impairment associated with inflammation through inhibition of the miR-93-mediated TLR4/MyD88/NF-κB signaling pathway in experimental VD.
Abstract: Background It is widely accepted that inflammation may contribute to cognitive impairment in patients with vascular dementia (VD). Our prior clinical researches have reported that acupuncture can alleviate cognitive function in VD, but the underlying mechanisms are still unclear. The purpose of this research was to explore whether acupuncture alleviates cognitive impairment by suppressing the microRNA-93- (miR-93-) mediated Toll-like receptor (TLR) signaling pathway, which triggers inflammatory responses in the central nervous system. Methods VD was established by permanent bilateral common carotid artery occlusion in male Wistar rats. Three days after operation, the rats began daily treatment with acupuncture for two weeks. The levels of miR-93, Toll-like receptors (TLR2 and TLR4), intracellular signaling molecules (myeloid differentiation factor 88 (MyD88) and nuclear factor-kappa B (NF-κB)), and inflammatory cytokines were subsequently detected. TLR4 colocalized with neurons, microglia, and astrocytes in the hippocampus was evaluated. Neuroinflammation and cognitive function were determined after intracerebroventricular injection of TLR4 antagonist TAK-242 or agonist lipopolysaccharide (LPS) with or without acupuncture. Results We found that acupuncture notably repressed the expression of inflammatory cytokines in the hippocampus and plasma of VD rats. The expression of TLR4, but not TLR2, was markedly downregulated by acupuncture, accompanied by a decrease in miR-93 and MyD88/NF-κB signaling pathway activation. The overexpression of TLR4 in microglia, but not in astrocytes and neurons, was reversed by acupuncture. Furthermore, intracerebroventricular injection of TAK-242 had similar effects to acupuncture on inflammation and cognitive function, while LPS injection abolished the beneficial effects of acupuncture. Conclusions Taken together, these findings provide evidence that acupuncture attenuates cognitive impairment associated with inflammation through inhibition of the miR-93-mediated TLR4/MyD88/NF-κB signaling pathway in experimental VD. Acupuncture serves as a promising alternative therapy and may be an underlying TLR4 inhibitor for the treatment of VD.
67 citations
Cites background from "MicroRNAs in Neuroinflammation: Imp..."
...By regulating the expression of multiple genes and pathways, miRNAs play a pivotal role in the pathogenesis of many neuroinflammatory disorders [55]....
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References
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7,744 citations
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4,490 citations
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TL;DR: Small non-coding RNAs that function as guide molecules in RNA silencing are involved in nearly all developmental and pathological processes in animals and their dysregulation is associated with many human diseases.
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4,256 citations
"MicroRNAs in Neuroinflammation: Imp..." refers background in this paper
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University Hospital Bonn1, University of California, Riverside2, Harvard University3, Case Western Reserve University4, University of Illinois at Chicago5, European Institute6, Stanford University7, VA Palo Alto Healthcare System8, Spanish National Research Council9, Cleveland Clinic Lerner Research Institute10, Hong Kong University of Science and Technology11, University of California, Los Angeles12, University of Southern Denmark13, University of Cambridge14, University of Manchester15, University of the Basque Country16, Ikerbasque17, RIKEN Brain Science Institute18, University of Eastern Finland19, University of Bonn20, University of Massachusetts Medical School21, Center of Advanced European Studies and Research22, University of Southern California23, University of South Florida24, Duke University25, Southampton General Hospital26, Moorgreen Hospital27, University of Southampton28, Louisiana State University29, Imperial College London30, Centre national de la recherche scientifique31, Karolinska Institutet32, Max Planck Society33, University of Tübingen34, University of Groningen35, University of Colorado Denver36, Douglas Mental Health University Institute37
TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.
Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.
3,947 citations
"MicroRNAs in Neuroinflammation: Imp..." refers background in this paper
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