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Nature Reviews. Immunology Feb 2024Cells can die as a consequence of being phagocytosed by other cells - a form of cell death that has been called phagotrophy, cell cannibalism, programmed cell removal... (Review)
Review
Cells can die as a consequence of being phagocytosed by other cells - a form of cell death that has been called phagotrophy, cell cannibalism, programmed cell removal and primary phagocytosis. However, these are all different manifestations of cell death by phagocytosis (termed 'phagoptosis' for short). The engulfed cells die as a result of cytotoxic oxidants, peptides and degradative enzymes within acidic phagolysosomes. Cell death by phagocytosis was discovered by Metchnikov in the 1880s, but was neglected until recently. It is now known to contribute to developmental cell death in nematodes, Drosophila and mammals, and is central to innate and adaptive immunity against pathogens. Cell death by phagocytosis mediates physiological turnover of erythrocytes and other leucocytes, making it the most abundant form of cell death in the mammalian body. Immunity against cancer is also partly mediated by macrophage phagocytosis of cancer cells, but cancer cells can also phagocytose host cells and other cancer cells in order to survive. Recent evidence indicates neurodegeneration and other neuropathologies can be mediated by microglial phagocytosis of stressed neurons. Thus, despite cell death by phagocytosis being poorly recognized, it is one of the oldest, commonest and most important forms of cell death.
Topics: Animals; Humans; Cell Death; Phagocytosis; Microglia; Macrophages; Neurons; Mammals
PubMed: 37604896
DOI: 10.1038/s41577-023-00921-6 -
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 -
Biochemistry and Cell Biology =... Feb 2019Phagocytosis is an evolutionarily conserved process. In Protozoa, phagocytosis fulfills a feeding mechanism, while in Metazoa, phagocytosis diversified to play multiple... (Review)
Review
Phagocytosis is an evolutionarily conserved process. In Protozoa, phagocytosis fulfills a feeding mechanism, while in Metazoa, phagocytosis diversified to play multiple organismal roles, including immune defence, tissue homeostasis, and remodeling. Accordingly, phagocytes display a high level of plasticity in their capacity to recognize, engulf, and process targets that differ in composition and morphology. Here, we review how phagocytosis adapts to its multiple roles and discuss in particular the effect of target morphology in phagocytic uptake and phagosome maturation.
Topics: Animals; Cell Physiological Phenomena; Humans; Phagocytosis; Phagosomes; Receptors, Cell Surface; Signal Transduction
PubMed: 29791809
DOI: 10.1139/bcb-2018-0008 -
Nature Communications Oct 2022Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely...
Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia are removed. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization. The engulfed microglial fragments are then degraded in astrocytes via RUBICON-dependent LC3-associated phagocytosis (LAP), a form of noncanonical autophagy. Interference with C4b-mediated engulfment and subsequent LAP disrupt the removal and degradation of microglial debris, respectively. Together, we elucidate the cellular and molecular mechanisms of microglial debris removal in mice, extending the knowledge on the maintenance of CNS homeostasis.
Topics: Animals; Mice; Microglia; Astrocytes; Phagocytosis; Autophagy; Central Nervous System; Intracellular Signaling Peptides and Proteins
PubMed: 36280666
DOI: 10.1038/s41467-022-33932-3 -
Cell and Tissue Research Sep 2019The uptake of macromolecules and larger energy-rich particles into the cell is known as phagocytosis. Phagocytosed material is enzymatically degraded in membrane-bound... (Review)
Review
The uptake of macromolecules and larger energy-rich particles into the cell is known as phagocytosis. Phagocytosed material is enzymatically degraded in membrane-bound vesicles of the endosome/lysosome system (intracellular digestion). Whereas most, if not all, cells of the animal body are equipped with the molecular apparatus for phagocytosis and intracellular digestion, a few cell types are specialized for a highly efficient mode of phagocytosis. These are the ("professional") macrophages, motile cells that seek out and eliminate pathogenic invaders or damaged cells. Macrophages form the backbone of the innate immune system. Developmentally, they derive from specialized compartments within the embryonic mesoderm and early vasculature as part of the process of hematopoiesis. Intensive research has revealed in detail molecular and cellular mechanisms of phagocytosis and intracellular digestion in macrophages. In contrast, little is known about a second type of cell that is "professionally" involved in phagocytosis, namely the "enteric phagocyte." Next to secretory (zymogenic) cells, enteric phagocytes form one of the two major cell types of the intestine of most invertebrate animals. Unlike vertebrates, these invertebrates only partially digest food material in the intestinal lumen. The resulting food particles are absorbed by phagocytosis or pinocytosis and digested intracellularly. In this review, we provide a brief overview of the enteric phagocytes described electron microscopically for diverse invertebrate clades, to then to compare these cells with the "canonical" phagocyte ultrastructure established for macrophages. In addition, we will review observations and speculations associated with the hypothesis that macrophages are evolutionarily derived from enteric phagocytes. This idea was already proposed in the late nineteenth century by Elias Metschnikoff who pioneered the research of phagocytosis for both macrophages and enteric phagocytes. We presume that modern approaches to better understand phagocytosis will be helped by considering the deep evolutionary relationship between the two cell types.
Topics: Animals; Biological Evolution; Macrophages; Phagocytosis
PubMed: 31485720
DOI: 10.1007/s00441-019-03096-6 -
Frontiers in Immunology 2021Mammalian phagocytes can phagocytose (i.e. eat) other mammalian cells in the body if they display certain signals, and this phagocytosis plays fundamental roles in... (Review)
Review
Mammalian phagocytes can phagocytose (i.e. eat) other mammalian cells in the body if they display certain signals, and this phagocytosis plays fundamental roles in development, cell turnover, tissue homeostasis and disease prevention. To phagocytose the correct cells, phagocytes must discriminate which cells to eat using a 'phagocytic code' - a set of over 50 known phagocytic signals determining whether a cell is eaten or not - comprising find-me signals, eat-me signals, don't-eat-me signals and opsonins. Most opsonins require binding to eat-me signals - for example, the opsonins galectin-3, calreticulin and C1q bind asialoglycan eat-me signals on target cells - to induce phagocytosis. Some proteins act as 'self-opsonins', while others are 'negative opsonins' or 'phagocyte suppressants', inhibiting phagocytosis. We review known phagocytic signals here, both established and novel, and how they integrate to regulate phagocytosis of several mammalian targets - including excess cells in development, senescent and aged cells, infected cells, cancer cells, dead or dying cells, cell debris and neuronal synapses. Understanding the phagocytic code, and how it goes wrong, may enable novel therapies for multiple pathologies with too much or too little phagocytosis, such as: infectious disease, cancer, neurodegeneration, psychiatric disease, cardiovascular disease, ageing and auto-immune disease.
Topics: Animals; Calreticulin; Cellular Senescence; Humans; Intercellular Adhesion Molecule-3; Opsonin Proteins; Phagocytosis; Phosphatidylserines; Polysaccharides; Signal Transduction; Synapses
PubMed: 34177884
DOI: 10.3389/fimmu.2021.629979 -
Nihon Yakurigaku Zasshi. Folia... 2023Neurons in the brain build circuits by synapsing with each other, and glial cells are involved in the formation and elimination of synapses. Glial cells include... (Review)
Review
Neurons in the brain build circuits by synapsing with each other, and glial cells are involved in the formation and elimination of synapses. Glial cells include microglia, astrocytes, and oligodendrocytes, each with distinctive functions supported by different gene expression patterns and morphologies, but all have been shown to regulate the number of synapses in the neuronal circuits through a common function, synaptic phagocytosis. It has also been reported that specific glial cell types phagocytose specific synapses in different brain regions and at different times, and some of the molecular mechanisms involved in each phagocytotic process have been elucidated. For example, microglia, the most frequently reported glial cell type in relation to synaptic phagocytes, are known to recognize various "eat me signals" including complement and phagocytose synapses, contributing to the refinement of neuronal circuits during development. More recently, astrocytes and oligodendrocyte precursor cells have also been shown to be involved in synaptic phagocytosis. Interestingly, there are also reports of different types of glial cells phagocytosing the same types of synapses. And in some cases, it has been suggested that different glial cell types regulate each other's synaptic phagocytosis. In this review, we will discuss the significance of synaptic phagocytosis by multiple types of glial cells by presenting recent studies on synaptic phagocytosis by glial cells.
Topics: Neuroglia; Neurons; Astrocytes; Microglia; Phagocytosis
PubMed: 37673608
DOI: 10.1254/fpj.23004 -
Medecine Sciences : M/S 2019Phagocytosis and macroautophagy, named here autophagy, are two essential mechanisms of lysosomal degradation of diverse cargos into membrane structures. Both mechanisms... (Review)
Review
Phagocytosis and macroautophagy, named here autophagy, are two essential mechanisms of lysosomal degradation of diverse cargos into membrane structures. Both mechanisms are involved in immune regulation and cell survival. However, phagocytosis triggers degradation of extracellular material whereas autophagy engulfs only cytoplasmic elements. Furthermore, activation and maturation of these two processes are different. LAP (LC3-associated phagocytosis) is a form of phagocytosis that uses components of the autophagy pathway. It can eliminate (i) pathogens, (ii) immune complexes, (iii) threatening neighbouring cells, dead or alive, and (iv) cell debris, such as POS (photoreceptor outer segment) and the midbody released at the end of mitosis. Cells have thus optimized their means of elimination of dangerous components by sharing some fundamental elements coming from the two main lysosomal degradation pathways.
Topics: Animals; Autophagy; Humans; Immune Evasion; Infections; Macrophages; Microtubule-Associated Proteins; Phagocytosis; Phagosomes
PubMed: 31532375
DOI: 10.1051/medsci/2019129 -
Seminars in Cell & Developmental Biology May 2020Phagocytes ingest, kill and degrade invading microbes in a process called phagocytosis. LC3-associated phagocytosis (LAP) combines the molecular machinery of... (Review)
Review
Phagocytes ingest, kill and degrade invading microbes in a process called phagocytosis. LC3-associated phagocytosis (LAP) combines the molecular machinery of phagocytosis with that of autophagy, the cellular pathway for ingestion of cytoplasmic components, resulting in the eponymous association of 'microtubule-associated proteins 1 A/1B light chain 3' (LC3) with the phagosomal membrane. The LC3-decorated phagosomes, or LAPosomes, show enhanced fusion with lysosomes resulting in enhanced killing and degradation of contained pathogens. Thus, LAP is a particularly microbicidal pathway. In this review, we discuss the molecular mechanisms involved in induction and execution of LAP and its crucial role in antimicrobial immunity against bacteria, fungi and parasites. As LAP has only recently been defined, we also point out the key open questions that remain to be answered.
Topics: Animals; Humans; Lysosomes; Microtubule-Associated Proteins; Phagocytosis; Phagosomes
PubMed: 31029766
DOI: 10.1016/j.semcdb.2019.04.016 -
Microbiology and Molecular Biology... Sep 2017How mitochondria came to reside within the cytosol of their host has been debated for 50 years. Though current data indicate that the last eukaryote common ancestor... (Review)
Review
How mitochondria came to reside within the cytosol of their host has been debated for 50 years. Though current data indicate that the last eukaryote common ancestor possessed mitochondria and was a complex cell, whether mitochondria or complexity came first in eukaryotic evolution is still discussed. In autogenous models (complexity first), the origin of phagocytosis poses the limiting step at eukaryote origin, with mitochondria coming late as an undigested growth substrate. In symbiosis-based models (mitochondria first), the host was an archaeon, and the origin of mitochondria was the limiting step at eukaryote origin, with mitochondria providing bacterial genes, ATP synthesis on internalized bioenergetic membranes, and mitochondrion-derived vesicles as the seed of the eukaryote endomembrane system. Metagenomic studies are uncovering new host-related archaeal lineages that are reported as complex or phagocytosing, although images of such cells are lacking. Here we review the physiology and components of phagocytosis in eukaryotes, critically inspecting the concept of a phagotrophic host. From ATP supply and demand, a mitochondrion-lacking phagotrophic archaeal fermenter would have to ingest about 34 times its body weight in prokaryotic prey to obtain enough ATP to support one cell division. It would lack chemiosmotic ATP synthesis at the plasma membrane, because phagocytosis and chemiosmosis in the same membrane are incompatible. It would have lived from amino acid fermentations, because prokaryotes are mainly protein. Its ATP yield would have been impaired relative to typical archaeal amino acid fermentations, which involve chemiosmosis. In contrast, phagocytosis would have had great physiological benefit for a mitochondrion-bearing cell.
Topics: Adenosine Triphosphate; Archaea; Biological Evolution; Endocytosis; Energy Metabolism; Eukaryotic Cells; Metagenomics; Mitochondria; Phagocytosis; Phylogeny; Prokaryotic Cells; Symbiosis
PubMed: 28615286
DOI: 10.1128/MMBR.00008-17