MicroRNA-124: A Key Player in Microglia-Mediated Inflammation in Neurological Diseases

Neurological disorders are mainly characterized by progressive neuron loss and neurological deterioration, which cause human disability and death. However, many types of neurological disorders have similar pathological mechanisms, including the neuroinflammatory response. Various microRNAs (miRs), such as miR-21, miR-124, miR-146a, and miR-132 were recently shown to affect a broad spectrum of biological functions in the central nervous system (CNS). Microglia are innate immune cells with important roles in the physiological and pathological activities of the CNS. Recently, abnormal expression of miR-124 was shown to be associated with the occurrence and development of various diseases in CNS via regulating microglia function. In addition, miR-124 is a promising biomarker and therapeutic target. Studies on the role of miR-124 in regulating microglia function involved in pathogenesis of neurological disorders at different stages will provide new ideas for the use of miR-124 as a therapeutic target for different CNS diseases.

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Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.789834 ◽

2021 ◽

Vol 13 ◽

Author(s):

Banglian Hu ◽

Shengshun Duan ◽

Ziwei Wang ◽

Xin Li ◽

Yuhang Zhou ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurological Disorders ◽

Neurological Diseases ◽

Colony Stimulating Factor ◽

Loss Of Function ◽

Axonal Spheroids ◽

The Central Nervous System ◽

Stimulating Factor

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

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Pericytes for Therapeutic Approaches to Ischemic Stroke

Frontiers in Neuroscience ◽

10.3389/fnins.2021.629297 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lu Cao ◽

Yanbo Zhou ◽

Mengguang Chen ◽

Li Li ◽

Wei Zhang

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Ischemic Stroke ◽

Therapeutic Target ◽

Neurological Disorders ◽

Neurovascular Unit ◽

Therapeutic Approaches ◽

Multipotent Cells ◽

The Central Nervous System

Pericytes are perivascular multipotent cells located on capillaries. Although pericytes are discovered in the nineteenth century, recent studies have found that pericytes play an important role in maintaining the blood—brain barrier (BBB) and regulating the neurovascular system. In the neurovascular unit, pericytes perform their functions by coordinating the crosstalk between endothelial, glial, and neuronal cells. Dysfunction of pericytes can lead to a variety of diseases, including stroke and other neurological disorders. Recent studies have suggested that pericytes can serve as a therapeutic target in ischemic stroke. In this review, we first summarize the biology and functions of pericytes in the central nervous system. Then, we focus on the role of dysfunctional pericytes in the pathogenesis of ischemic stroke. Finally, we discuss new therapies for ischemic stroke based on targeting pericytes.

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The Dichotomous Role of Inflammation in the CNS: A Mitochondrial Point of View

Biomolecules ◽

10.3390/biom10101437 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1437

Author(s):

Bianca Vezzani ◽

Marianna Carinci ◽

Simone Patergnani ◽

Matteo P. Pasquin ◽

Annunziata Guarino ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Epileptic Seizures ◽

Point Of View ◽

Innate Immune ◽

Molecular Signaling ◽

Therapeutic Approaches ◽

Neuroinflammatory Response ◽

The Central Nervous System

Innate immune response is one of our primary defenses against pathogens infection, although, if dysregulated, it represents the leading cause of chronic tissue inflammation. This dualism is even more present in the central nervous system, where neuroinflammation is both important for the activation of reparatory mechanisms and, at the same time, leads to the release of detrimental factors that induce neurons loss. Key players in modulating the neuroinflammatory response are mitochondria. Indeed, they are responsible for a variety of cell mechanisms that control tissue homeostasis, such as autophagy, apoptosis, energy production, and also inflammation. Accordingly, it is widely recognized that mitochondria exert a pivotal role in the development of neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases, as well as in acute brain damage, such in ischemic stroke and epileptic seizures. In this review, we will describe the role of mitochondria molecular signaling in regulating neuroinflammation in central nervous system (CNS) diseases, by focusing on pattern recognition receptors (PRRs) signaling, reactive oxygen species (ROS) production, and mitophagy, giving a hint on the possible therapeutic approaches targeting mitochondrial pathways involved in inflammation.

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Gut–Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions

International Journal of Molecular Sciences ◽

10.3390/ijms21207551 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7551

Author(s):

Kanmani Suganya ◽

Byung-Soo Koo

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Neurological Disorders ◽

Fecal Microbiota Transplantation ◽

Neurological Diseases ◽

Fecal Microbiota ◽

Normal Brain ◽

Brain Functions ◽

The Central Nervous System

The gut microbiome acts as an integral part of the gastrointestinal tract (GIT) that has the largest and vulnerable surface with desirable features to observe foods, nutrients, and environmental factors, as well as to differentiate commensals, invading pathogens, and others. It is well-known that the gut has a strong connection with the central nervous system (CNS) in the context of health and disease. A healthy gut with diverse microbes is vital for normal brain functions and emotional behaviors. In addition, the CNS controls most aspects of the GI physiology. The molecular interaction between the gut/microbiome and CNS is complex and bidirectional, ensuring the maintenance of gut homeostasis and proper digestion. Besides this, several mechanisms have been proposed, including endocrine, neuronal, toll-like receptor, and metabolites-dependent pathways. Changes in the bidirectional relationship between the GIT and CNS are linked with the pathogenesis of gastrointestinal and neurological disorders; therefore, the microbiota/gut-and-brain axis is an emerging and widely accepted concept. In this review, we summarize the recent findings supporting the role of the gut microbiota and immune system on the maintenance of brain functions and the development of neurological disorders. In addition, we highlight the recent advances in improving of neurological diseases by probiotics/prebiotics/synbiotics and fecal microbiota transplantation via the concept of the gut–brain axis.

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Microbiota-Immune System Interactions in Human Neurological Disorders

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200726222138 ◽

2020 ◽

Vol 19 (7) ◽

pp. 509-526

Author(s):

Qin Huang ◽

Fang Yu ◽

Di Liao ◽

Jian Xia

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Neurological Disorders ◽

Brain Function ◽

Neurological Diseases ◽

Host Immune System ◽

Gut Dysbiosis ◽

Characteristic Features ◽

Novel Therapeutic Strategies

: Recent studies implicate microbiota-brain communication as an essential factor for physiology and pathophysiology in brain function and neurodevelopment. One of the pivotal mechanisms about gut to brain communication is through the regulation and interaction of gut microbiota on the host immune system. In this review, we will discuss the role of microbiota-immune systeminteractions in human neurological disorders. The characteristic features in the development of neurological diseases include gut dysbiosis, the disturbed intestinal/Blood-Brain Barrier (BBB) permeability, the activated inflammatory response, and the changed microbial metabolites. Neurological disorders contribute to gut dysbiosis and some relevant metabolites in a top-down way. In turn, the activated immune system induced by the change of gut microbiota may deteriorate the development of neurological diseases through the disturbed gut/BBB barrier in a down-top way. Understanding the characterization and identification of microbiome-immune- brain signaling pathways will help us to yield novel therapeutic strategies by targeting the gut microbiome in neurological disease.

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The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

International Journal of Molecular Sciences ◽

10.3390/ijms22052578 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2578

Author(s):

Trim Lajqi ◽

Christian Marx ◽

Hannes Hudalla ◽

Fabienne Haas ◽

Silke Große ◽

...

Keyword(s):

Oxygen Consumption ◽

Immune Tolerance ◽

Immune Cells ◽

Low Dose ◽

Innate Immune ◽

Immune Memory ◽

Innate Immune Cells ◽

Atp Production ◽

Dose Dependent

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.

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Aggravation of autism-like behavior in BTBR T+tf/J mice by environmental pollutant, di-(2-ethylhexyl) phthalate: Role of nuclear factor erythroid 2-related factor 2 and oxidative enzymes in innate immune cells and cerebellum

International Immunopharmacology ◽

10.1016/j.intimp.2020.107323 ◽

2021 ◽

Vol 91 ◽

pp. 107323

Author(s):

Ahmed Nadeem ◽

Sheikh F. Ahmad ◽

Naif O. Al-Harbi ◽

Sabry M. Attia ◽

Saleh A. Bakheet ◽

...

Keyword(s):

Immune Cells ◽

Environmental Pollutant ◽

Innate Immune ◽

Oxidative Enzymes ◽

Related Factor ◽

Innate Immune Cells ◽

Nuclear Factor ◽

Ethylhexyl Phthalate

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Intestinal Microbiota as an Alternative Therapeutic Target for Epilepsy

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2016/9032809 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 12

Author(s):

Jiaying Wu ◽

Yuyu Zhang ◽

Hongyu Yang ◽

Yuefeng Rao ◽

Jing Miao ◽

...

Keyword(s):

Immune Responses ◽

Intestinal Microbiota ◽

Neurological Disorders ◽

Digestive System ◽

Hygiene Hypothesis ◽

Host Susceptibility ◽

Immune Disorders ◽

The Central Nervous System ◽

Symbiotic Microbiota

Epilepsy is one of the most widespread serious neurological disorders, and an aetiological explanation has not been fully identified. In recent decades, a growing body of evidence has highlighted the influential role of autoimmune mechanisms in the progression of epilepsy. The hygiene hypothesis draws people’s attention to the association between gut microbes and the onset of multiple immune disorders. It is also believed that, in addition to influencing digestive system function, symbiotic microbiota can bidirectionally and reversibly impact the programming of extraintestinal pathogenic immune responses during autoimmunity. Herein, we investigate the concept that the diversity of parasitifer sensitivity to commensal microbes and the specific constitution of the intestinal microbiota might impact host susceptibility to epilepsy through promotion of Th17 cell populations in the central nervous system (CNS).

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Pannexin-1 Channels as Mediators of Neuroinflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22105189 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5189

Author(s):

Joon Ho Seo ◽

Miloni S. Dalal ◽

Jorge E. Contreras

Keyword(s):

Immune Cells ◽

Neurological Diseases ◽

Atp Release ◽

Innate Immune ◽

Innate Immune Cells ◽

Damage Site ◽

Pannexin 1 ◽

Cytokines And Chemokines ◽

Secondary Damage ◽

Dying Cells

Neuroinflammation is a major component of central nervous system (CNS) injuries and neurological diseases, including Alzheimer’s disease, multiple sclerosis, neuropathic pain, and brain trauma. The activation of innate immune cells at the damage site causes the release of pro-inflammatory cytokines and chemokines, which alter the functionality of nearby tissues and might mediate the recruitment of leukocytes to the injury site. If this process persists or is exacerbated, it prevents the adequate resolution of the inflammation, and ultimately enhances secondary damage. Adenosine 5′ triphosphate (ATP) is among the molecules released that trigger an inflammatory response, and it serves as a chemotactic and endogenous danger signal. Extracellular ATP activates multiple purinergic receptors (P2X and P2Y) that have been shown to promote neuroinflammation in a variety of CNS diseases. Recent studies have shown that Pannexin-1 (Panx1) channels are the principal conduits of ATP release from dying cells and innate immune cells in the brain. Herein, we review the emerging evidence that directly implicates Panx-1 channels in the neuroinflammatory response in the CNS.

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