-
CNS Neuroscience & Therapeutics Mar 2020A large number of families worldwide suffer from the physical and mental burden posed by stroke. An increasing number of studies aimed at the prevention and treatment of... (Review)
Review
A large number of families worldwide suffer from the physical and mental burden posed by stroke. An increasing number of studies aimed at the prevention and treatment of stroke have been conducted. Specifically, manipulating the immune response to stroke is under intense investigation. Microglia are the principal immune cells in the brain and are the first line of defense against the pathophysiology induced by stroke. Increasing evidence has suggested that microglia play diverse roles that depend on dynamic interactions with neurons, astrocytes, and other neighboring cells both in the normal brain and under pathological conditions, including stroke. Moreover, there are dynamic alterations in microglial functions with respect to aging and sex differences in the human brain, which offer a deep understanding of the conditions of stroke patients of different ages and sex. Hence, we review the dynamic microglial reactions caused by aging, sex, and crosstalk with neighboring cells both in normal conditions and after stroke and relevant potential interventions.
Topics: Aging; Animals; Brain; Humans; Microglia; Neurons; Sex Characteristics; Stroke
PubMed: 32064759
DOI: 10.1111/cns.13291 -
Biomolecules Jul 2021Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by... (Review)
Review
Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by other glial cell types such as microglia, the brain-resident, macrophage-like innate immune cells. In this review, we summarize how oligodendrocytes orchestrate myelination, and especially myelin repair after damage, and present novel aspects of oligodendroglial functions. We emphasize the contribution of microglia in the generation and regeneration of myelin by discussing their beneficial and detrimental roles, especially in remyelination, underlining the cellular and molecular components involved. Finally, we present recent findings towards human stem cell-derived preclinical models for the study of microglia in human pathologies and on the role of microbiome on glial cell functions.
Topics: Animals; Demyelinating Diseases; Humans; Microbiota; Microglia; Myelin Sheath; Oligodendroglia; Regeneration; Remyelination; Stem Cells
PubMed: 34356682
DOI: 10.3390/biom11071058 -
Stem Cell Reviews and Reports Feb 2022Neonatal hypoxia-ischemia encephalopathy (HIE) refers to a brain injury in term infants that can lead to death or lifelong neurological deficits such as cerebral palsy... (Review)
Review
Neonatal hypoxia-ischemia encephalopathy (HIE) refers to a brain injury in term infants that can lead to death or lifelong neurological deficits such as cerebral palsy (CP). The pathogenesis of this disease involves multiple cellular and molecular events, notably a neuroinflammatory response driven partly by microglia, the brain resident macrophages. Treatment options are currently very limited, but stem cell (SC) therapy holds promise, as beneficial outcomes are reported in animal studies and to a lesser degree in human trials. Among putative mechanisms of action, immunomodulation is considered a major contributor to SC associated benefits. The goal of this review is to examine whether microglia is a cellular target of SC-mediated immunomodulation and whether the recruitment of microglia is linked to brain repair. We will first provide an overview on microglial activation in the rodent model of neonatal HI, and highlight its sensitivity to developmental age. Two complementary questions are then addressed: (i) do immune-related treatments impact microglia and provide neuroprotection, (ii) does stem cell treatment modulates microglia? Finally, the immune-related findings in patients enrolled in SC based clinical trials are discussed. Our review points to an impact of SCs on the microglial phenotype, but heterogeneity in experimental designs and methodological limitations hamper our understanding of a potential contribution of microglia to SC associated benefits. Thorough analyses of the microglial phenotype are warranted to better address the relevance of the neuroimmune crosstalk in brain repair and improve or advance the development of SC protocols in humans.
Topics: Animals; Animals, Newborn; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Ischemia; Microglia; Neuroprotection; Stem Cells
PubMed: 34382141
DOI: 10.1007/s12015-021-10213-y -
Journal of Cerebral Blood Flow and... Dec 2020
Topics: Brain; Humans; Microglia
PubMed: 33208002
DOI: 10.1177/0271678X20968993 -
Cells Dec 2023Synapses are the fundamental structures of neural circuits that control brain functions and behavioral and cognitive processes. Synapses undergo formation, maturation,... (Review)
Review
Synapses are the fundamental structures of neural circuits that control brain functions and behavioral and cognitive processes. Synapses undergo formation, maturation, and elimination mainly during postnatal development via a complex interplay with neighboring astrocytes and microglia that, by shaping neural connectivity, may have a crucial role in the strengthening and weakening of synaptic functions, that is, the functional plasticity of synapses. Indeed, an increasing number of studies have unveiled the roles of microglia and astrocytes in synapse formation, maturation, and elimination as well as in regulating synaptic function. Over the past 15 years, the mechanisms underlying the microglia- and astrocytes-dependent regulation of synaptic plasticity have been thoroughly studied, and researchers have reported that the disruption of these glial cells in early postnatal development may underlie the cause of synaptic dysfunction that leads to neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia.
Topics: Humans; Microglia; Autism Spectrum Disorder; Schizophrenia; Synapses; Neuroglia
PubMed: 38132147
DOI: 10.3390/cells12242827 -
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 -
Molecules (Basel, Switzerland) Oct 2022Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, but effective treatments are lacking, and neuroinflammation plays a key role in the pathogenesis. In... (Review)
Review
Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, but effective treatments are lacking, and neuroinflammation plays a key role in the pathogenesis. In the innate immune response to cerebral hemorrhage, microglia first appear around the injured tissue and are involved in the inflammatory cascade response. Microglia respond to acute brain injury by being activated and polarized to either a typical M1-like (pro-inflammatory) or an alternative M2-like (anti-inflammatory) phenotype. These two polarization states produce pro-inflammatory or anti-inflammatory. With the discovery of the molecular mechanisms and key signaling molecules related to the polarization of microglia in the brain, some targets that regulate the polarization of microglia to reduce the inflammatory response are considered a treatment for secondary brain tissue after ICH damage effective strategies. Therefore, how to promote the polarization of microglia to the M2 phenotype after ICH has become the focus of attention in recent years. This article reviews the mechanism of action of microglia's M1 and M2 phenotypes in secondary brain injury after ICH. Moreover, it discusses compounds and natural pharmaceutical ingredients that can polarize the M1 to the M2 phenotype.
Topics: Humans; Microglia; Cerebral Hemorrhage; Stroke; Brain Injuries; Anti-Inflammatory Agents; Pharmaceutical Preparations
PubMed: 36296682
DOI: 10.3390/molecules27207080 -
Glia Dec 2018Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the... (Review)
Review
Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.
Topics: Animals; Cellular Reprogramming; Encephalitis; Humans; Microglia
PubMed: 30195261
DOI: 10.1002/glia.23484 -
Current Opinion in Genetics &... Feb 2024Microglia are the major immune cells of the central nervous system (CNS) that perform numerous adaptive functions required for normal CNS development and homeostasis but... (Review)
Review
Microglia are the major immune cells of the central nervous system (CNS) that perform numerous adaptive functions required for normal CNS development and homeostasis but are also linked to neurodegenerative and behavioral diseases. Microglia development and function are strongly influenced by brain environmental signals that are integrated at the level of transcriptional enhancers to drive specific programs of gene expression. Here, we describe a conceptual framework for how lineage-determining and signal-dependent transcription factors interact to select and regulate the ensembles of enhancers that determine microglia development and function. We then highlight recent findings that advance these concepts and conclude with a consideration of open questions that represent some of the major hurdles to be addressed in the future.
Topics: Humans; Microglia; Neurodegenerative Diseases; Central Nervous System; Brain; Phenotype
PubMed: 38171044
DOI: 10.1016/j.gde.2023.102146 -
Ophthalmic Research 2023Uveitis, a complicated group of ocular inflammatory diseases, can be affected by massive pathogenic contributors such as infection, autoimmunity, and genetics. Although... (Review)
Review
Uveitis, a complicated group of ocular inflammatory diseases, can be affected by massive pathogenic contributors such as infection, autoimmunity, and genetics. Although it is well known that many pathological changes, including disorders of the immune system and disruption of the blood-retinal barrier, count much in the onset and progression of uveitis, there is a paucity of safe and effective treatments, which has exceedingly hindered the appropriate treatment of uveitis. As innate immune cells in the retina, microglia occupy a salient position in retinal homeostasis. Many studies have reported the activation of microglia in uveitis and the mitigation of uveitis by interfering with microglial reactivity, which strongly implicates microglia as a therapeutic target. However, it has been increasingly recognized that microglia are a nonhomogeneous population under different physiological and pathological conditions, which makes it essential to thoroughly have knowledge of their specific characteristics. The paper outlines the various properties of activated microglia in uveitis, summarizes the connections between their polarization patterns and the manifestations of uveitis, and ultimately is intended to enhance the understanding of microglial versatility and expedite the exploration of promising strategies for visual protection.
Topics: Humans; Microglia; Uveitis; Retina
PubMed: 37666222
DOI: 10.1159/000531156