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Journal of Cerebral Blood Flow and... Dec 2020
Topics: Brain; Humans; Microglia
PubMed: 33208002
DOI: 10.1177/0271678X20968993 -
Journal of Neurochemistry Oct 2023Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration.... (Review)
Review
Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain-infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro- and anti-inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro-inflammatory activation is associated with decreased mitochondrial respiration, whereas anti-inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post-traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non-resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post-traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.
Topics: Animals; Mice; Microglia; Neurochemistry; Neuroinflammatory Diseases; Brain Injuries, Traumatic; Anti-Inflammatory Agents; Mice, Inbred C57BL
PubMed: 37759406
DOI: 10.1111/jnc.15959 -
Neurochemistry International Nov 2019In the last decade tremendous progress has been made in understanding how the immune system reacts to insults. During this progress it became obvious that those immune... (Review)
Review
In the last decade tremendous progress has been made in understanding how the immune system reacts to insults. During this progress it became obvious that those immune responses are tightly regulated and cross-linked with distinct metabolic changes in immune cells. Extensive research has been conducted mainly on subtypes of T cells, which use different metabolic pathways during differentiation processes and activation states. In addition, it has also been established later, that the innate immune cell lineage of myeloid cells includes a variety of different subsets of bone marrow-derived as well as tissue-specific macrophages, which elicit much more functions than simply killing bacteria. To execute this high variety of functions, also macrophages use different metabolic pathways and are tightly regulated by key metabolic regulators, such as the mechanistic target of rapamycin (mTOR). Upon activation, metabolic changes within the cell occur to meet the requirements of the phenotypic switch. In addition, metabolic changes correlate with the ability of innate immune cells to show hallmarks of adaptive immune responses. Little is known about specific metabolic changes of myeloid cells and specifically microglia in vivo. Microglia are key players in neurodegenerative and neuroinflammatory diseases and have become a major target of medical research. Here, we review the existing data on microglia metabolism and the connection of microglia phenotypes with neuroinflammatory and neurodegenerative diseases. Lastly, we will discuss how our knowledge about the cellular metabolism might be used to develop new treatment options for neurological diseases.
Topics: Animals; Brain; Energy Metabolism; Humans; Inflammation; Microglia; Neurodegenerative Diseases
PubMed: 30423423
DOI: 10.1016/j.neuint.2018.11.006 -
Molecular Psychiatry Jan 2023Microglia are resident immune cells in the central nervous system, playing critical roles in brain development and homeostasis. Increasing evidence has implicated... (Review)
Review
Microglia are resident immune cells in the central nervous system, playing critical roles in brain development and homeostasis. Increasing evidence has implicated microglia dysfunction in the pathogenesis of various brain disorders ranging from psychiatric disorders to neurodegenerative diseases. Using a human cell-based model to illuminate the functional mechanisms of microglia will promote pathological studies and drug development. The recently developed microglia-containing human brain organoids (MC-HBOs), in-vitro three-dimensional cell cultures that recapitulate key features of the human brain, have provided a new avenue to model brain development and pathology. However, MC-HBOs generated from different methods differ in the origin, proportion, and fidelity of microglia within the organoids, and may have produced inconsistent results. To help researchers to develop a robust and reproducible model that recapitulates in-vivo signatures of human microglia to study brain development and pathology, this review summarized the current methods used to generate MC-HBOs and provided opinions on the use of MC-HBOs for disease modeling and functional studies.
Topics: Humans; Microglia; Brain; Central Nervous System; Neurodegenerative Diseases; Organoids
PubMed: 36474001
DOI: 10.1038/s41380-022-01892-1 -
Central Nervous System Agents in... 2022Neuroinflammation is a key component in the etiopathogenesis of neurological diseases and brain aging. This process involves the brain immune system that modulates... (Review)
Review
BACKGROUND
Neuroinflammation is a key component in the etiopathogenesis of neurological diseases and brain aging. This process involves the brain immune system that modulates synaptic functions and protects neurons from infection or damage. Hence, the knowledge of neuroinflammation related pathways and modulation by drugs or natural compounds is functional to developing therapeutic strategies aimed at preserving, maintaining and restoring brain health.
OBJECTIVE
This review article summarizes the basics of neuroinflammation and related signaling pathways, the success of the dietary intervention in clinical practice and the possible development of RNA-based strategies for treating neurological diseases.
METHODS
Pubmed search from 2012 to 2022 with the keywords neuroinflammation and molecular mechanisms in combination with diet, miRNA and non-coding RNA.
RESULTS
Glial cells-play a crucial role in neuroinflammation, but several pathways can be activated in response to different inflammatory stimuli, inducing cell death by apoptosis, pyroptosis or necroptosis. The dietary intervention has immunomodulatory effects and could limit the inflammatory process induced by microglia and astrocytes. Thus by inhibiting neuroinflammation and improving the symptoms of a variety of neurological diseases, diet exerts pleiotropic neuroprotective effects independently from the spectrum of pathophysiological mechanisms underlying the specific disorder. Furthermore, data from animal models revealed that altered expression of specific noncoding RNAs, in particular microRNAs, contributes to neuroinflammatory diseases; consequently, RNA-based strategies may be promising to alleviate the consequences of neuroinflammation.
CONCLUSION
Further studies are needed to identify the molecular pathways and the new pharmacological targets in neuroinflammation to lay the basis for more effective and selective therapies to be applied, in parallel to dietary intervention, in the treatment of neuroinflammation-based diseases.
Topics: Animals; Neuroinflammatory Diseases; Microglia; Astrocytes; Neuroprotective Agents; MicroRNAs; Nervous System Diseases; Inflammation
PubMed: 36177627
DOI: 10.2174/1871524922666220929153215 -
International Journal of Molecular... Dec 2023Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition,... (Review)
Review
Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.
Topics: Child; Humans; Autism Spectrum Disorder; Microglia; Schizophrenia; Brain; Neurons
PubMed: 38139124
DOI: 10.3390/ijms242417297 -
Ageing Research Reviews Jan 2024Central nervous system (CNS) diseases have become one of the leading causes of death in the global population. The pathogenesis of CNS diseases is complicated, so it is... (Review)
Review
Central nervous system (CNS) diseases have become one of the leading causes of death in the global population. The pathogenesis of CNS diseases is complicated, so it is important to find the patterns of the disease to improve the treatment strategy. Microglia are considered to be a double-edged sword, playing both harmful and beneficial roles in CNS diseases. Therefore, it is crucial to understand the progression of the disease and the changes in the polar phenotype of microglia to provide guidance in the treatment of CNS diseases. Microglia activation may evolve into different phenotypes: M1 and M2 types. We focused on the roles that M1 and M2 microglia play in regulating intercellular dialogues, pathological reactions and specific diseases in CNS diseases. Importantly, we summarized the strategies used to modulate the polarization phenotype of microglia, including traditional pharmacological modulation, biological therapies, and physical strategies. This review will contribute to the development of potential strategies to modulate microglia polarization phenotypes and provide new alternative therapies for CNS diseases.
Topics: Humans; Microglia; Central Nervous System Diseases; Phenotype
PubMed: 38065225
DOI: 10.1016/j.arr.2023.102160 -
Neuropathology and Applied Neurobiology Feb 2021Motor Neuron Disease (MND) is a fatal neurodegenerative condition, which is characterized by the selective loss of the upper and lower motor neurons. At the sites of... (Review)
Review
Motor Neuron Disease (MND) is a fatal neurodegenerative condition, which is characterized by the selective loss of the upper and lower motor neurons. At the sites of motor neuron injury, accumulation of activated microglia, the primary immune cells of the central nervous system, is commonly observed in both human post mortem studies and animal models of MND. Microglial activation has been found to correlate with many clinical features and importantly, the speed of disease progression in humans. Both anti-inflammatory and pro-inflammatory microglial responses have been shown to influence disease progression in humans and models of MND. As such, microglia could both contribute to and protect against inflammatory mechanisms of pathogenesis in MND. While murine models have characterized the microglial response to MND, these studies have painted a complex and often contradictory picture, indicating a need for further characterization in humans. This review examines the potential role microglia play in MND in human and animal studies. Both the pro-inflammatory and anti-inflammatory responses will be addressed, throughout the course of disease, followed by the potential of microglia as a target in the development of disease-modifying treatments for MND.
Topics: Animals; Humans; Microglia; Motor Neuron Disease
PubMed: 32594542
DOI: 10.1111/nan.12640 -
Journal of Neuroinflammation May 2023Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis.
BACKGROUND
Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis.
METHOD
In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope.
RESULTS
We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states.
CONCLUSION
In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.
Topics: Humans; Child; Adolescent; Transcriptome; Microglia; Longevity; Phagocytosis; Sequence Analysis, RNA
PubMed: 37254100
DOI: 10.1186/s12974-023-02809-7 -
Cells Jun 2021Microglia are the resident immune cells of the central nervous system (CNS), including the retina. Similar to brain microglia, retinal microglia are responsible for... (Review)
Review
Microglia are the resident immune cells of the central nervous system (CNS), including the retina. Similar to brain microglia, retinal microglia are responsible for retinal surveillance, rapidly responding to changes in the environment by altering morphotype and function. Microglia become activated in inflammatory responses in neurodegenerative diseases, including multiple sclerosis (MS). When activated by stress stimuli, retinal microglia change their morphology and activity, with either beneficial or harmful consequences. In this review, we describe characteristics of CNS microglia, including those in the retina, with a focus on their morphology, activation states and function in health, ageing, MS and other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, glaucoma and retinitis pigmentosa, to highlight their activity in disease. We also discuss contradictory findings in the literature and the potential ways of reducing inconsistencies in future by using standardised methodology, e.g., automated algorithms, to enable a more comprehensive understanding of this exciting area of research.
Topics: Aging; Alzheimer Disease; Animals; Brain; Central Nervous System; Humans; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Parkinson Disease; Retina
PubMed: 34203793
DOI: 10.3390/cells10061507