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Nature Reviews. Molecular Cell Biology Jul 2020Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian... (Review)
Review
Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis. Efferocytosis is performed by macrophages and to a lesser extent by other 'professional' phagocytes (such as monocytes and dendritic cells) and 'non-professional' phagocytes, such as epithelial cells. Recent discoveries have shed light on this process and how it functions to maintain tissue homeostasis, tissue repair and organismal health. Here, we outline the mechanisms of efferocytosis, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and highlight the pathophysiological consequences that can arise when this process is abrogated.
Topics: Animals; Apoptosis; Homeostasis; Host-Pathogen Interactions; Humans; Inflammation; Macrophages; Phagocytes; Phagocytosis; Signal Transduction
PubMed: 32251387
DOI: 10.1038/s41580-020-0232-1 -
Cell Jun 2017Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell...
Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
Topics: Alzheimer Disease; Animals; Humans; Mice; Mice, Transgenic; Microglia; Neurodegenerative Diseases; Phagocytes; Receptors, Immunologic; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 28602351
DOI: 10.1016/j.cell.2017.05.018 -
Cell Jun 2023Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal...
Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.
Topics: Animals; Mice; Antifungal Agents; Candidiasis; Complement C5; Phagocytes
PubMed: 37220746
DOI: 10.1016/j.cell.2023.04.031 -
Cells Aug 2021Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as... (Review)
Review
Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as "resting", amoeboid and phagocytic microglia were viewed as "activated". In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an "expiration date" limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer's disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease.
Topics: Animals; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Antigens, Differentiation, Myelomonocytic; Brain; Calcium-Binding Proteins; Histocompatibility Antigens Class II; Humans; Membrane Proteins; Microfilament Proteins; Microglia; Nerve Tissue Proteins; Neurodegenerative Diseases; Phagocytes; Phenotype; Receptors, Purinergic P2Y12; Signal Transduction
PubMed: 34571885
DOI: 10.3390/cells10092236 -
Nature Neuroscience Mar 2023Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals...
Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa, Grn and Ctsb in presence of amyloid-β oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell-cell interaction analyses reveal that perivascular SPP1 induces microglial phagocytic states in the hippocampus of a mouse model of AD. Altogether, we suggest a functional role for SPP1 in perivascular cells-to-microglia crosstalk, whereby SPP1 modulates microglia-mediated synaptic engulfment in mouse models of AD.
Topics: Mice; Animals; Alzheimer Disease; Microglia; Osteopontin; Phagocytes; Macrophages; Phagocytosis; Disease Models, Animal; Amyloid beta-Peptides
PubMed: 36747024
DOI: 10.1038/s41593-023-01257-z -
Microbiology Spectrum Mar 2019has evolved to become the single greatest cause of death from an infectious agent. The pathogen spends most of its infection cycle in its human host within a phagocyte.... (Review)
Review
has evolved to become the single greatest cause of death from an infectious agent. The pathogen spends most of its infection cycle in its human host within a phagocyte. The bacterium has evolved to block the normal maturation and acidification of its phagosome and resides in a vacuole contiguous with the early endosomal network. Cytokine-mediated activation of the host cell can overcome this blockage, and an array of antimicrobial responses can limit its survival. The survival of in its host cell is fueled predominantly by fatty acids and cholesterol. The ability of to degrade sterols is an unusual metabolic characteristic that was likely retained from a saprophytic ancestor. Recent results with fluorescent reporter strains demonstrate that bacterial survival differs with the host macrophage population. Tissue-resident alveolar macrophages, which are biased towards an alternatively activated, M2-like phenotype, are more permissive to bacterial growth than monocyte-derived, inflammatory, M1-like interstitial macrophages. The differential growth of the bacterium in these different phagocyte populations appears to be linked to host cell metabolism.
Topics: Animals; Anti-Bacterial Agents; Cytokines; Host-Pathogen Interactions; Humans; Macrophages; Microbial Viability; Mycobacterium tuberculosis; Phagocytes; Phagosomes; Tuberculosis; Vacuoles
PubMed: 30848232
DOI: 10.1128/microbiolspec.BAI-0001-2019 -
Immunological Reviews Mar 2015Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they... (Review)
Review
Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics.
Topics: Animals; Cell Communication; Host-Pathogen Interactions; Humans; Immunity, Innate; Lysosomes; Macrophage Activation; Macrophages; Metals; Mycobacterium tuberculosis; Phagocytes; Phagocytosis; Phagosomes; Tuberculosis
PubMed: 25703560
DOI: 10.1111/imr.12266 -
Frontiers in Immunology 2020Phagocytosis is a cellular process for ingesting and eliminating particles larger than 0.5 μm in diameter, including microorganisms, foreign substances, and apoptotic... (Review)
Review
Phagocytosis is a cellular process for ingesting and eliminating particles larger than 0.5 μm in diameter, including microorganisms, foreign substances, and apoptotic cells. Phagocytosis is found in many types of cells and it is, in consequence an essential process for tissue homeostasis. However, only specialized cells termed professional phagocytes accomplish phagocytosis with high efficiency. Macrophages, neutrophils, monocytes, dendritic cells, and osteoclasts are among these dedicated cells. These professional phagocytes express several phagocytic receptors that activate signaling pathways resulting in phagocytosis. The process of phagocytosis involves several phases: i) detection of the particle to be ingested, ii) activation of the internalization process, iii) formation of a specialized vacuole called phagosome, and iv) maturation of the phagosome to transform it into a phagolysosome. In this review, we present a general view of our current understanding on cells, phagocytic receptors and phases involved in phagocytosis.
Topics: Apoptosis; Humans; Models, Immunological; Pathogen-Associated Molecular Pattern Molecules; Phagocytes; Phagocytosis; Phagosomes; Receptors, Complement; Receptors, IgG; Receptors, Immunologic; Receptors, Pattern Recognition; Signal Transduction
PubMed: 32582172
DOI: 10.3389/fimmu.2020.01066 -
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 -
Nature Communications Nov 2022Perivascular macrophages (pvMs) are associated with cerebral vasculature and mediate brain drainage and immune regulation. Here, using reporter mouse models, whole brain...
Perivascular macrophages (pvMs) are associated with cerebral vasculature and mediate brain drainage and immune regulation. Here, using reporter mouse models, whole brain and section immunofluorescence, flow cytometry, and single cell RNA sequencing, besides the Lyve1F4/80CD206CX3CR1 pvMs, we identify a CX3CR1 pvM population that shares phagocytic functions and location. Furthermore, the brain parenchyma vasculature mostly hosts Lyve1MHCII pvMs with low to intermediate CD45 expression. Using the double Cx3cr1 x Cx3cr1-Cre;Rosa reporter mice for finer mapping of the lineages, we establish that CD45CX3CR1 pvMs are derived from CX3CR1 precursors and require PU.1 during their ontogeny. In parallel, results from the Cxcr4-CreErt2;Rosa26 lineage tracing model support a bone marrow-independent replenishment of all Lyve1 pvMs in the adult mouse brain. Lastly, flow cytometry and 3D immunofluorescence analysis uncover increased percentage of pvMs following photothrombotic induced stroke. Our results thus show that the parenchymal pvM population is more heterogenous than previously described, and includes a CD45 and CX3CR1 pvM population.
Topics: Animals; Mice; Macrophages; Leukocyte Count; Phagocytes; Flow Cytometry; Brain
PubMed: 36450771
DOI: 10.1038/s41467-022-35166-9