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Nature Reviews. Immunology Apr 2020The clearance of apoptotic cells by professional and non-professional phagocytes - a process termed 'efferocytosis' - is essential for the maintenance of tissue... (Review)
Review
The clearance of apoptotic cells by professional and non-professional phagocytes - a process termed 'efferocytosis' - is essential for the maintenance of tissue homeostasis. Accordingly, defective efferocytosis underlies a growing list of chronic inflammatory diseases. Although much has been learnt about the mechanisms of apoptotic cell recognition and uptake, several key areas remain incompletely understood. This Review focuses on new discoveries related to how phagocytes process the metabolic cargo they receive during apoptotic cell uptake; the links between efferocytosis and the resolution of inflammation in health and disease; and the roles of efferocytosis in host defence. Understanding these aspects of efferocytosis sheds light on key physiological and pathophysiological processes and suggests novel therapeutic strategies for diseases driven by defective efferocytosis and impaired inflammation resolution.
Topics: Apoptosis; Homeostasis; Humans; Inflammation; Phagocytes; Phagocytosis
PubMed: 31822793
DOI: 10.1038/s41577-019-0240-6 -
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 -
International Journal of Molecular... Jan 2022Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that... (Review)
Review
Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)-including phagocytes and viable tumour cells-and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with "double-edged" consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.
Topics: Animals; Apoptosis; Cell Proliferation; Cell Survival; Humans; Immunity, Innate; Neoplasms; Phagocytes; Tumor Microenvironment
PubMed: 35163253
DOI: 10.3390/ijms23031328 -
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 -
Theranostics 2021Macrophages phagocytize pathogens to initiate innate immunity and products from the tumor microenvironment (TME) to mediate tumor immunity. The loss of tumor-associated... (Review)
Review
Macrophages phagocytize pathogens to initiate innate immunity and products from the tumor microenvironment (TME) to mediate tumor immunity. The loss of tumor-associated macrophage (TAM)-mediated immune responses results in immune suppression. To reverse this immune disorder, the regulatory mechanism of TAMs in the TME needs to be clarified. Immune molecules (cytokines and chemokines) from TAMs and the TME have been widely accepted as mutual mediators of signal transduction in the past few decades. Recently, researchers have tried to seek the intrinsic mechanism of TAM phenotypic and functional changes through metabolic connections. Numerous metabolites derived from the TME have been identified that induce the cell-cell crosstalk with TAMs. The bulk tumor cells, immune cells, and stromal cells produce metabolites in the TME that are involved in the metabolic regulation of TAMs. Meanwhile, some products from TAMs regulate the biological functions of the tumor as well. Here, we review the recent reports demonstrating the metabolic regulation between TME and TAMs.
Topics: Animals; Humans; Immunity, Innate; Neoplasms; Signal Transduction; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 33391518
DOI: 10.7150/thno.51777 -
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 -
Cell Dec 2022Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of "efferocytosis." Defects in efferocytosis are now...
Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of "efferocytosis." Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis, denoted "chimeric receptor for efferocytosis" (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis. In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity, and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation.
Topics: Animals; Mice; Macrophages; Phagocytosis; Inflammation; Phagocytes; Carrier Proteins; Apoptosis; Adaptor Proteins, Signal Transducing
PubMed: 36563662
DOI: 10.1016/j.cell.2022.11.029 -
Nature Methods Aug 2019Accurately modeling cellular response to perturbations is a central goal of computational biology. While such modeling has been based on statistical, mechanistic and...
Accurately modeling cellular response to perturbations is a central goal of computational biology. While such modeling has been based on statistical, mechanistic and machine learning models in specific settings, no generalization of predictions to phenomena absent from training data (out-of-sample) has yet been demonstrated. Here, we present scGen (https://github.com/theislab/scgen), a model combining variational autoencoders and latent space vector arithmetics for high-dimensional single-cell gene expression data. We show that scGen accurately models perturbation and infection response of cells across cell types, studies and species. In particular, we demonstrate that scGen learns cell-type and species-specific responses implying that it captures features that distinguish responding from non-responding genes and cells. With the upcoming availability of large-scale atlases of organs in a healthy state, we envision scGen to become a tool for experimental design through in silico screening of perturbation response in the context of disease and drug treatment.
Topics: Algorithms; Animals; Computational Biology; Computer Simulation; Gene Expression Profiling; Humans; Leukocytes, Mononuclear; Machine Learning; Mice; Phagocytes; Single-Cell Analysis; Species Specificity; Transcriptome
PubMed: 31363220
DOI: 10.1038/s41592-019-0494-8 -
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