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Immunity Jul 2021Neutrophils are immune cells with unusual biological features that furnish potent antimicrobial properties. These cells phagocytose and subsequently kill prokaryotic and... (Review)
Review
Neutrophils are immune cells with unusual biological features that furnish potent antimicrobial properties. These cells phagocytose and subsequently kill prokaryotic and eukaryotic organisms very efficiently. Importantly, it is not only their ability to attack microbes within a constrained intracellular compartment that endows neutrophils with antimicrobial function. They can unleash their effectors into the extracellular space, where, even post-mortem, their killing machinery can endure and remain functional. The antimicrobial activity of neutrophils must not be misconstrued as being microbe specific and should be viewed more generally as biotoxic. Outside of fighting infections, neutrophils can harness their noxious machinery in other contexts, like cancer. Inappropriate or dysregulated neutrophil activation damages the host and contributes to autoimmune and inflammatory disease. Here we review a number of topics related to neutrophil biology based on contemporary findings.
Topics: Animals; Extracellular Space; Humans; Inflammation; Neutrophil Activation; Neutrophils; Phagocytosis
PubMed: 34260886
DOI: 10.1016/j.immuni.2021.06.006 -
Nature Reviews. Immunology Sep 2023Macrophages are innate immune cells that form a 3D network in all our tissues, where they phagocytose dying cells and cell debris, immune complexes, bacteria and other... (Review)
Review
Macrophages are innate immune cells that form a 3D network in all our tissues, where they phagocytose dying cells and cell debris, immune complexes, bacteria and other waste products. Simultaneously, they produce growth factors and signalling molecules - such activities not only promote host protection in response to invading microorganisms but are also crucial for organ development and homeostasis. There is mounting evidence of macrophages orchestrating fundamental physiological processes, such as blood vessel formation, adipogenesis, metabolism and central and peripheral neuronal function. In parallel, novel methodologies have led to the characterization of tissue-specific macrophages, with distinct subpopulations of these cells showing different developmental trajectories, transcriptional programmes and life cycles. Here, we summarize our growing knowledge of macrophage diversity and how macrophage subsets orchestrate tissue development and function. We further interrelate macrophage ontogeny with their core functions across tissues, that is, the signalling events within the macrophage niche that may control organ functionality during development, homeostasis and ageing. Finally, we highlight the open questions that will need to be addressed by future studies to better understand the tissue-specific functions of distinct macrophage subsets.
Topics: Humans; Macrophages; Phagocytosis; Signal Transduction; Biology
PubMed: 36922638
DOI: 10.1038/s41577-023-00848-y -
Journal of Cerebral Blood Flow and... Sep 2022Stroke, including ischemic stroke and hemorrhagic stroke can cause massive neuronal death and disruption of brain structure, which is followed by secondary inflammatory...
Stroke, including ischemic stroke and hemorrhagic stroke can cause massive neuronal death and disruption of brain structure, which is followed by secondary inflammatory injury initiated by pro-inflammatory molecules and cellular debris. Phagocytic clearance of cellular debris by microglia, the brain's scavenger cells, is pivotal for neuroinflammation resolution and neurorestoration. However, microglia can also exacerbate neuronal loss by phagocytosing stressed-but-viable neurons in the penumbra, thereby expanding the injury area and hindering neurofunctional recovery. Microglia constantly patrol the central nervous system using their processes to scour the cellular environment and start or cease the phagocytosis progress depending on the "eat me" or "don't eat me'' signals on cellular surface. An optimal immune response requires a delicate balance between different phenotypic states to regulate neuro-inflammation and facilitate reconstruction after stroke. Here, we examine the literature and discuss the molecular mechanisms and cellular pathways regulating microglial phagocytosis, their resulting effects in brain injury and neural regeneration, as well as the potential therapeutic targets that might modulate microglial phagocytic activity to improve neurological function after stroke.
Topics: Brain Ischemia; Humans; Microglia; Neurons; Phagocytosis; Stroke
PubMed: 35491825
DOI: 10.1177/0271678X221098841 -
Cell and Tissue Research Sep 2019Living cells depend on a constant supply of energy-rich organic molecules from the environment. Small molecules pass into the interior of the cell via simple diffusion...
Living cells depend on a constant supply of energy-rich organic molecules from the environment. Small molecules pass into the interior of the cell via simple diffusion or active transport carried out by membrane bound transporters; macromolecules, or entire cells, are taken up by endocytosis/phagocytosis, and are degraded intracellularly in specialized membrane bound compartments (lysosomes). Whereas all cells are capable of transporting molecules through the membrane, the efficient procurement, digestion and uptake of nutrients have become the function of specialized cell types and organs, forming the digestive system in multicellular animals. In mammals, for example, the digestive system is comprised of glandular organs with classes of cells specialized in the secretion of enzymes for the extracellular digestion of food particles (e.g., exocrine cells of the salivary gland, pancreas), as well as other organs with absorptive function (e.g., small intestine). Numerous other cell types, such as smooth muscle cells, neurons and enteroendocrine cells, are associated with glandular cells and intestinal cells to promote the digestive process.
Topics: Animals; Biological Evolution; Digestion; Digestive System; Immune System; Phagocytosis
PubMed: 31478136
DOI: 10.1007/s00441-019-03102-x -
Cell Oct 2018Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic...
Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2 breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.
Topics: Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; B7-H1 Antigen; Breast Neoplasms; Cell Line, Tumor; Cytophagocytosis; DNA-Binding Proteins; Disease Models, Animal; Female; Humans; Immunotherapy; Killer Cells, Natural; Lymphoma; Macrophages; Mice; Mice, Inbred NOD; Mice, SCID; Phagocytosis; Phagosomes; Receptors, IgG
PubMed: 30290143
DOI: 10.1016/j.cell.2018.09.007 -
CNS Neuroscience & Therapeutics Sep 2022Phagocytosis is the cellular digestion of extracellular particles, such as pathogens and dying cells, and is a key element in the evolution of central nervous system... (Review)
Review
AIMS
Phagocytosis is the cellular digestion of extracellular particles, such as pathogens and dying cells, and is a key element in the evolution of central nervous system (CNS) disorders. Microglia and macrophages are the professional phagocytes of the CNS. By clearing toxic cellular debris and reshaping the extracellular matrix, microglia/macrophages help pilot the brain repair and functional recovery process. However, CNS resident and invading immune cells can also magnify tissue damage by igniting runaway inflammation and phagocytosing stressed-but viable-neurons.
DISCUSSION
Microglia/macrophages help mediate intercellular communication and react quickly to the "find-me" signals expressed by dead/dying neurons. The activated microglia/macrophages then migrate to the injury site to initiate the phagocytic process upon encountering "eat-me" signals on the surfaces of endangered cells. Thus, healthy cells attempt to avoid inappropriate engulfment by expressing "do not-eat-me" signals. Microglia/macrophages also have the capacity to phagocytose immune cells that invade the injured brain (e.g., neutrophils) and to regulate their pro-inflammatory properties. During brain recovery, microglia/macrophages engulf myelin debris, initiate synaptogenesis and neurogenesis, and sculpt a favorable extracellular matrix to support network rewiring, among other favorable roles. Here, we review the multilayered nature of phagocytotic microglia/macrophages, including the molecular and cellular mechanisms that govern microglia/macrophage-induced phagocytosis in acute brain injury, and discuss strategies that tap into the therapeutic potential of this engulfment process.
CONCLUSION
Identification of biological targets that can temper neuroinflammation after brain injury without hindering the essential phagocytic functions of microglia/macrophages will expedite better medical management of the stroke recovery stage.
Topics: Brain; Brain Injuries; Central Nervous System Diseases; Humans; Macrophages; Microglia; Phagocytes; Phagocytosis
PubMed: 35751629
DOI: 10.1111/cns.13899 -
Neuron Oct 2018Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific...
Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs.
Topics: Animals; CD47 Antigen; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurogenesis; Neuronal Plasticity; Phagocytosis; Receptors, Immunologic; Synapses
PubMed: 30308165
DOI: 10.1016/j.neuron.2018.09.017 -
Nature Neuroscience Sep 2020During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similarly to neurons and synapses, excess myelin sheaths are produced and selectively...
During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similarly to neurons and synapses, excess myelin sheaths are produced and selectively eliminated, but how elimination occurs is unknown. Microglia, the resident immune cells of the central nervous system, engulf surplus neurons and synapses. To determine whether microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. By using a combination of optical, genetic, chemogenetic, and behavioral approaches, we reveal that neuronal activity bidirectionally balances microglial association with neuronal cell bodies and myelin phagocytosis in the optic tectum. Furthermore, multiple strategies to deplete microglia resulted in oligodendrocytes maintaining excessive and ectopic myelin. Our work reveals a neuronal activity-regulated role for microglia in modifying developmental myelin targeting by oligodendrocytes.
Topics: Animals; Animals, Genetically Modified; Microglia; Myelin Sheath; Neurogenesis; Neurons; Oligodendroglia; Phagocytosis; Spinal Cord; Superior Colliculi; Zebrafish
PubMed: 32632287
DOI: 10.1038/s41593-020-0654-2 -
Journal For Immunotherapy of Cancer Dec 2020Tumor-associated macrophage (TAM) phagocytic activity is emerging as a new mechanism to harness for cancer treatment. Currently, many approaches are investigated at the... (Review)
Review
Tumor-associated macrophage (TAM) phagocytic activity is emerging as a new mechanism to harness for cancer treatment. Currently, many approaches are investigated at the preclinical level and some modalities have now reached clinical trials, including the targeting of the phagocytosis inhibitor CD47. The rationale for increasing TAM phagocytic activity is to improve innate anticancer immunity, and to promote T-cell mediated adaptive immune responses. In this context, a clear understanding of the impact of TAM phagocytosis on both innate and adaptive immunity is critical. Indeed, uncertainties persist regarding the capacity of TAM to present tumor antigens to CD8 T cells by cross-presentation. This process is critical for an optimal cytotoxic T-cell immune response and can be mediated by dendritic cells but also potentially by macrophages. In addition, the engulfment of cancer cells affects TAM functionality, as apoptotic cell uptake (a process termed efferocytosis) promotes macrophage anti-inflammatory functions. Because of the abundance of TAM in most solid tumors and the common use of apoptosis inducers such as radiotherapy to treat patients with cancer, efferocytosis potentially affects the overall immune balance within the tumor microenvironment (TME). In this review, we will discuss how cancer cell phagocytosis by TAM impacts antitumor immunity. First, we will focus on the potential of the phagocytic activity of TAM per se to control tumor progression. Second, we will examine the potential of TAM to act as antigen presenting cells for tumor specific CD8 T cells, considering the different characteristics of this process in the tumor tissue and at the molecular level. Finally, we will see how phagocytosis and efferocytosis affect TAM functionality and how these mechanisms impact on antitumor immunity. A better understanding of these aspects will enable us to better predict and interpret the consequences of cancer therapies on the immune status of the TME. Future cancer treatment regimens can thereby be designed to not only impact directly on cancer cells, but also to favorably modulate TAM phagocytic activity to benefit from the potential of this central immune player to achieve more potent therapeutic efficacy.
Topics: Disease Progression; Humans; Macrophages; Phagocytosis; Tumor Microenvironment
PubMed: 33335026
DOI: 10.1136/jitc-2020-001408 -
Molecular Neurobiology Jun 2014Microglia, the resident macrophages of the central nervous system, rapidly activate in nearly all kinds of neurological diseases. These activated microglia become highly... (Review)
Review
Microglia, the resident macrophages of the central nervous system, rapidly activate in nearly all kinds of neurological diseases. These activated microglia become highly motile, secreting inflammatory cytokines, migrating to the lesion area, and phagocytosing cell debris or damaged neurons. During the past decades, the secretory property and chemotaxis of microglia have been well-studied, while relatively less attention has been paid to microglial phagocytosis. So far there is no obvious concordance with whether it is beneficial or detrimental in tissue repair. This review focuses on phagocytic phenotype of microglia in neurological diseases such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, traumatic brain injury, ischemic and other brain diseases. Microglial morphological characteristics, involved receptors and signaling pathways, distribution variation along with time and space changes, and environmental factors that affecting phagocytic function in each disease are reviewed. Moreover, a comparison of contributions between macrophages from peripheral circulation and the resident microglia to these pathogenic processes will also be discussed.
Topics: Animals; Central Nervous System Diseases; Humans; Microglia; Phagocytosis; Signal Transduction
PubMed: 24395130
DOI: 10.1007/s12035-013-8620-6