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Trends in Pharmacological Sciences Aug 2022Microglia, brain resident immune cells, modulate development, activity, and plasticity of the central nervous system. Mechanistically implicated in numerous neurological... (Review)
Review
Microglia, brain resident immune cells, modulate development, activity, and plasticity of the central nervous system. Mechanistically implicated in numerous neurological pathologies, microglia emerge as strong contenders for novel neurotherapies. Shifting away from merely an attenuation of excessive microglial inflammatory and phagocytic activities, current therapies aim toward targeting the complex context-dependent microglial heterogeneity, unveiled by large-scale genetic studies and emerging single-cell analyses. Although lacking the necessary selectivity, initial therapies attempting to target specific state-associated microglial properties and functions (e.g., inflammatory activity, phagocytosis, proliferation, metabolism, or surveillance) are currently under pre- or even clinical (Phase I-IV) investigation. Here, we provide an update on current microglial therapeutic research and discuss what the future in the field might look like.
Topics: Brain; Drug Delivery Systems; Humans; Microglia; Phagocytosis
PubMed: 35031144
DOI: 10.1016/j.tips.2021.11.006 -
Journal of Neurochemistry Nov 2023In the central nervous system, microglia are responsible for removing infectious agents, damaged/dead cells, and amyloid plaques by phagocytosis. Other cell types, such...
In the central nervous system, microglia are responsible for removing infectious agents, damaged/dead cells, and amyloid plaques by phagocytosis. Other cell types, such as astrocytes, are also recently recognized to show phagocytotic activity under some conditions. Oligodendrocyte precursor cells (OPCs), which belong to the same glial cell family as microglia and astrocytes, may have similar functions. However, it remains largely unknown whether OPCs exhibit phagocytic activity against foreign materials like microglia. To answer this question, we examined the phagocytosis activity of OPCs using primary rat OPC cultures. Since innate phagocytosis activity could trigger cell death pathways, we also investigated whether participating in phagocytosis activity may lead to OPC cell death. Our data shows that cultured OPCs phagocytosed myelin-debris-rich lysates prepared from rat corpus callosum, without progressing to cell death. In contrast to OPCs, mature oligodendrocytes did not show phagocytotic activity against the bait. OPCs also exhibited phagocytosis towards lysates of rat brain cortex and cell membrane debris from cultured astrocytes, but the percentage of OPCs that phagocytosed beta-amyloid was much lower than the myelin debris. We then conducted RNA-seq experiments to examine the transcriptome profile of OPC cultures and found that myelination- and migration-associated genes were downregulated 24 h after phagocytosis. On the other hand, there were a few upregulated genes in OPCs 24 h after phagocytosis. These data confirm that OPCs play a role in debris removal and suggest that OPCs may remain in a quiescent state after phagocytosis.
Topics: Rats; Animals; Oligodendrocyte Precursor Cells; Cell Differentiation; Myelin Sheath; Oligodendroglia; Phagocytosis; Cells, Cultured
PubMed: 37874764
DOI: 10.1111/jnc.15994 -
Nephron 2022Various forms of cell death have been identified, and billions of cells die during development and daily in adult organisms. Clearing dead cells and associated cellular... (Review)
Review
Various forms of cell death have been identified, and billions of cells die during development and daily in adult organisms. Clearing dead cells and associated cellular debris is an integral part of tissue homeostasis. While diverse types of phagocytes remove various forms of dying cells during acute kidney injury (AKI), it remains unknown whether boosting removal of a specific form of dying cell would provide a benefit and which cell type should be targeted for phagocytosis-mediated therapy. As there is a lack of viable strategies for the prevention and treatment of AKI, novel therapies and innovative approaches are required. There is a strong demand on developing and analyzing novel models to boost, monitor, and stop phagocytosis of dying cells.
Topics: Acute Kidney Injury; Apoptosis; Cell Death; Female; Humans; Male; Phagocytes; Phagocytosis
PubMed: 34284391
DOI: 10.1159/000517731 -
Advances in Experimental Medicine and... 2020Although we know a wealth of detail about the molecular and cell biology of phagocytosis, there are many unsolved mysteries remaining. In this final chapter, some...
Although we know a wealth of detail about the molecular and cell biology of phagocytosis, there are many unsolved mysteries remaining. In this final chapter, some important may be tangential) questions are raised, that the bulk of researchers are not really addressing. In this chapter, some suggestions are given for this type of "blue skies" future work. These include new approaches to understanding phagocytosis and the possibility that this new knowledge may provide a solution to anti-microbial resistance. This future phagocytosis research would have an impact, not only on our understanding of phagocytosis, but potentially on the future of human health.
Topics: Humans; Phagocytosis
PubMed: 32399831
DOI: 10.1007/978-3-030-40406-2_10 -
Glia Jun 2022Elimination of dead or live cells take place in both a healthy and diseased central nervous system (CNS). Dying or dead cells are quickly cleared by phagocytosis for the... (Review)
Review
Elimination of dead or live cells take place in both a healthy and diseased central nervous system (CNS). Dying or dead cells are quickly cleared by phagocytosis for the maintenance of a healthy CNS or for recovery after injury. Live cells or parts thereof, such as the synapses and myelin, are appropriately eliminated by phagocytosis to maintain or refine neural networks during development and adulthood. Microglia, the specific population of resident macrophages in the CNS, are classically considered as primary phagocytes; however, astrocytes have also been highlighted as phagocytes in the last decade. Phagocytic targets and receptors are reported to be mostly common between astrocytes and microglia, which raises the question of how astrocytic phagocytosis differs from microglial phagocytosis, and how these two phagocytic systems cooperate. In this review, we address the consequences of astrocytic phagocytosis, particularly focusing on these elusive points.
Topics: Astrocytes; Central Nervous System; Microglia; Phagocytes; Phagocytosis
PubMed: 35142399
DOI: 10.1002/glia.24145 -
Blood Jun 2022
Topics: B7-H1 Antigen; Extracellular Vesicles; Humans; Macrophages; Neoplasms; Phagocytosis; Tumor Suppressor Protein p53
PubMed: 35737407
DOI: 10.1182/blood.2022016100 -
Journal of Neuroscience Research Feb 2020Microglia are the innate immune cells of the brain, which maintain homeostasis by constantly scanning and surveying the environment with their highly ramified processes.... (Review)
Review
Microglia are the innate immune cells of the brain, which maintain homeostasis by constantly scanning and surveying the environment with their highly ramified processes. In order to exert this function, they need to phagocytose synapses as well as debris and dead cells, a process that is further amplified in pathological conditions. Importantly, it has been shown that microglia phagocytic capacity is altered in the course of neurodegenerative disease, for which aging is one of the highest risk factors. Thus, understanding how phagocytosis is impaired during aging is a priority for future research. Advances in this area are expected to significantly contribute to our understanding of normal cognition during aging, as well as changes that take place in age-associated neurodegenerative diseases. In this review, we will summarize the current knowledge on how phagocytosis is executed and affected by aging or in age-associated neurological disorders, such as Alzheimer's disease (AD). Furthermore, we will summarize both protective and deleterious consequences of altered phagocytosis in AD and where relevant in other neurodegenerative diseases.
Topics: Aging; Alzheimer Disease; Animals; Brain; Humans; Microglia; Phagocytosis
PubMed: 30942936
DOI: 10.1002/jnr.24419 -
Neurological Sciences : Official... Mar 2022Efferocytosis has a critical role in maintaining tissues and organs' homeostasis by removing apoptotic cells. It is essential for human health, and disturbances in... (Review)
Review
Efferocytosis has a critical role in maintaining tissues and organs' homeostasis by removing apoptotic cells. It is essential for human health, and disturbances in efferocytosis may result indifferent illnesses. In case of inadequate clearance of the dead cells, the content in the cells would be released. In fact, it induces some damages to the tissue and leads to the prolonged inflammation, so unsuitable phagocytosis of the apoptotic cells is involved in occurrence as well as expansion of numerous human chronic inflammatory diseases. Studies have shown age dependence of the neuro-degenerative diseases, which are largely due to the neuro-inflammation and the loss of neurons and thus cause the brain's functional disorders. Efferocytosis is coupled to anti-inflammatory responses that contribute to the elimination of the dying neurons in neuro-degenerative diseases, so its disruption may make a risk factor in numerous human chronic inflammatory diseases such as multiple sclerosis, Alzheimer's disease, glioblastoma, and Rett syndrome. This study is a review of the efferocytosis molecular pathways and their role in neuro-degenerative diseases in order to discover a new treatment option to cure patients.
Topics: Apoptosis; Homeostasis; Humans; Inflammation; Macrophages; Phagocytosis
PubMed: 35059903
DOI: 10.1007/s10072-021-05835-6 -
Cell Host & Microbe Aug 2021Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated...
Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase. Physiologically, autocrine IL-6/JAK2/Ninein axis orchestrates microtubule organization and dynamics regulating ERK recruitment to the phagosome and LC3 phagosome (LAPosome) formation. In sepsis, loss of IL-6 signaling specifically abrogates microtubule-mediated trafficking of ERK, leading to defective activation of LAP and impaired killing of bacterial and fungal pathogens by monocytes/macrophages, which can be selectively restored by IL-6 supplementation. Our work uncovers a molecular pathway linking IL-6 signaling with LAP and provides insight into the mechanisms underlying immunoparalysis in sepsis.
Topics: Aspergillus fumigatus; Cytokines; Cytoskeletal Proteins; Humans; Interleukin-6; Janus Kinase 2; Macrophages; Microtubule-Associated Proteins; Monocytes; Nuclear Proteins; Phagocytes; Phagocytosis; Sepsis; Signal Transduction
PubMed: 34214493
DOI: 10.1016/j.chom.2021.06.002 -
International Journal of Molecular... Aug 2019The immune response is essential to protect organisms from infection and an altered self. An organism's overall metabolic status is now recognized as an important and... (Review)
Review
The immune response is essential to protect organisms from infection and an altered self. An organism's overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic organelles with a central role in the synthesis and turnover of complex lipids and reactive species. Peroxisomes have recently been identified as pivotal regulators of immune functions and inflammation in the development and during infection, defining a new branch of immunometabolism. This review summarizes the current evidence that has helped to identify peroxisomes as central regulators of immunity and highlights the peroxisomal proteins and metabolites that have acquired relevance in human pathologies for their link to the development of inflammation, neuropathies, aging and cancer. This review then describes how peroxisomes govern immune signaling strategies such as phagocytosis and cytokine production and their relevance in fighting bacterial and viral infections. The mechanisms by which peroxisomes either control the activation of the immune response or trigger cellular metabolic changes that activate and resolve immune responses are also described.
Topics: Aging; Animals; Biomarkers; Disease Susceptibility; Energy Metabolism; Host-Pathogen Interactions; Humans; Immunity; Immunomodulation; Inflammation; Peroxisomes; Phagocytosis; Signal Transduction
PubMed: 31398943
DOI: 10.3390/ijms20163877