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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 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 -
The Journal of Experimental Medicine May 2020Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the...
Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.
Topics: ATP Binding Cassette Transporter 1; Animals; Brain; Cell Line; Cholesterol; Endocytosis; Fatty Acids; Foam Cells; Humans; Inflammation; Macrophages; Mice; Microglia; Myelin Sheath; Phagocytes; Phenotype; Protein Kinase C-delta; Stearoyl-CoA Desaturase
PubMed: 32097464
DOI: 10.1084/jem.20191660 -
American Journal of Respiratory Cell... Jul 2017The current paradigm in macrophage biology is that some tissues mainly contain macrophages from embryonic origin, such as microglia in the brain, whereas other tissues...
The current paradigm in macrophage biology is that some tissues mainly contain macrophages from embryonic origin, such as microglia in the brain, whereas other tissues contain postnatal-derived macrophages, such as the gut. However, in the lung and in other organs, such as the skin, there are both embryonic and postnatal-derived macrophages. In this study, we demonstrate in the steady-state lung that the mononuclear phagocyte system is comprised of three newly identified interstitial macrophages (IMs), alveolar macrophages, dendritic cells, and few extravascular monocytes. We focused on similarities and differences between the three IM subtypes, specifically, their phenotype, location, transcriptional signature, phagocytic capacity, turnover, and lack of survival dependency on fractalkine receptor, CXCR1. Pulmonary IMs were located in the bronchial interstitium but not the alveolar interstitium. At the transcriptional level, all three IMs displayed a macrophage signature and phenotype. All IMs expressed MER proto-oncogene, tyrosine kinase, CD64, CD11b, and CXCR1, and were further distinguished by differences in cell surface protein expression of CD206, Lyve-1, CD11c, CCR2, and MHC class II, along with the absence of Ly6C, Ly6G, and Siglec F. Most intriguingly, in addition to the lung, similar phenotypic populations of IMs were observed in other nonlymphoid organs, perhaps highlighting conserved functions throughout the body. These findings promote future research to track four distinct pulmonary macrophages and decipher the division of labor that exists between them.
Topics: Animals; Bone Marrow Cells; Dendritic Cells; Gene Expression Profiling; Lung; Macrophages; Macrophages, Alveolar; Mice, Inbred C57BL; Organ Specificity; Phagocytes; Phenotype; Transcription, Genetic
PubMed: 28257233
DOI: 10.1165/rcmb.2016-0361OC -
Neuron Nov 2022CNS-resident macrophages-including parenchymal microglia and border-associated macrophages (BAMs)-contribute to neuronal development and health, vascularization, and... (Review)
Review
CNS-resident macrophages-including parenchymal microglia and border-associated macrophages (BAMs)-contribute to neuronal development and health, vascularization, and tissue integrity at steady state. Border-patrolling mononuclear phagocytes such as dendritic cells and monocytes confer important immune functions to the CNS, protecting it from pathogenic threats including aberrant cell growth and brain malignancies. Even though we have learned much about the contribution of lymphocytes to CNS pathologies, a better understanding of differential roles of tissue-resident and -invading phagocytes is slowly emerging. In this perspective, we propose that in CNS neuroinflammatory diseases, tissue-resident macrophages (TRMs) contribute to the clearing of debris and resolution of inflammation, whereas blood-borne phagocytes are drivers of immunopathology. We discuss the remaining challenges to resolve which specialized mononuclear phagocyte populations are driving or suppressing immune effector function, thereby potentially dictating the outcome of autoimmunity or brain cancer.
Topics: Humans; Mononuclear Phagocyte System; Microglia; Phagocytes; Macrophages; Monocytes; Brain Neoplasms
PubMed: 36327896
DOI: 10.1016/j.neuron.2022.10.005 -
Current Opinion in Immunology Oct 2019Transition metal ions are essential to bacterial pathogens and their hosts alike but are harmful in excess. In an effort to curtail the replication of intracellular... (Review)
Review
Transition metal ions are essential to bacterial pathogens and their hosts alike but are harmful in excess. In an effort to curtail the replication of intracellular bacteria, host phagocytes exploit both the essentiality and toxicity of transition metals. In the paradigmatic description of nutritional immunity, iron and manganese are withheld from phagosomes to starve microbial invaders of these nutrients. Conversely, the destructive properties of copper and zinc appear to be harnessed by phagocytes, where these metals are delivered in excess to phagosomes to intoxicate internalized bacteria. Here, we briefly summarize key players in metal withholding from intracellular pathogens, before focusing on recent findings supporting the function of copper and zinc as phagocyte antimicrobial effectors. The mechanisms of copper and zinc toxicity are explored, along with strategies employed by intracellular bacterial pathogens to avoid killing by these metals.
Topics: Anti-Bacterial Agents; Bacteria; Copper; Phagocytes; Zinc
PubMed: 31063946
DOI: 10.1016/j.coi.2019.04.002 -
Microbiology Spectrum Apr 2016Since the ability of some cells to engulf particulate material was observed before Metchnikoff, he did not "discover" phagocytosis, as is sometimes mentioned in... (Review)
Review
Since the ability of some cells to engulf particulate material was observed before Metchnikoff, he did not "discover" phagocytosis, as is sometimes mentioned in textbooks. Rather, he assigned to particle internalization the role of defending the host against noxious stimuli, which represented a new function relative to the previously recognized task of intracellular digestion. With this proposal, Metchnikoff built the conceptual framework within which immunity could finally be seen as an active host function triggered by noxious stimuli. In this sense, Metchnikoff can be rightly regarded as the father of all immunological sciences and not only of innate immunity or myeloid cell biology. Moreover, the recognition properties of his phagocyte fit surprisingly well with recent discoveries and modern models of immune sensing. For example, rather than assigning to immune recognition exclusively the function of eliminating nonself components (as others did after him), Metchnikoff viewed phagocytes as homeostatic agents capable of monitoring the internal environment and promoting tissue remodeling, thereby continuously defining the identity of the organism. No doubt, Metchnikoff's life and creativity can provide, still today, a rich source of inspiration.
Topics: Allergy and Immunology; History, 19th Century; History, 20th Century; Humans; Immunity, Innate; Myeloid Cells; Phagocytes; Phagocytosis
PubMed: 27227301
DOI: 10.1128/microbiolspec.MCHD-0009-2015 -
Frontiers in Immunology 2020Phagocytes are highly motile immune cells that ingest and clear microbial invaders, harmful substances, and dying cells. Their function is critically dependent on the... (Review)
Review
Phagocytes are highly motile immune cells that ingest and clear microbial invaders, harmful substances, and dying cells. Their function is critically dependent on the expression of chemokine receptors, a class of G-protein-coupled receptors (GPCRs). Chemokine receptors coordinate the recruitment of phagocytes and other immune cells to sites of infection and damage, modulate inflammatory and wound healing responses, and direct cell differentiation, proliferation, and polarization. Besides, a structurally diverse group of atypical chemokine receptors (ACKRs) are unable to signal in G-protein-dependent fashion themselves but can shape chemokine gradients by fine-tuning the activity of conventional chemokine receptors. The optically transparent zebrafish embryos and larvae provide a powerful system to visualize phagocytes during development and study them as key elements of the immune response in real-time. In this review, we discuss how the zebrafish model has furthered our understanding of the role of two main classes of chemokine receptors, the CC and CXC subtypes, in phagocyte biology. We address the roles of the receptors in the migratory properties of phagocytes in zebrafish models for cancer, infectious disease, and inflammation. We illustrate how studies in zebrafish enable visualizing the contribution of chemokine receptors and ACKRs in shaping self-generated chemokine gradients of migrating cells. Taking the functional antagonism between two paralogs of the CXCR3 family as an example, we discuss how the duplication of chemokine receptor genes in zebrafish poses challenges, but also provides opportunities to study sub-functionalization or loss-of-function events. We emphasize how the zebrafish model has been instrumental to prove that the major determinant for the functional outcome of a chemokine receptor-ligand interaction is the cell-type expressing the receptor. Finally, we highlight relevant homologies and analogies between mammalian and zebrafish phagocyte function and discuss the potential of zebrafish models to further advance our understanding of chemokine receptors in innate immunity and disease.
Topics: Animals; Humans; Immunity, Innate; Inflammation; Macrophages; Neoplasms; Phagocytes; Receptors, Chemokine; Wounds and Injuries; Zebrafish
PubMed: 32161595
DOI: 10.3389/fimmu.2020.00325 -
Cells May 2021Phagocytosis by glial cells has been shown to play an important role in maintaining brain homeostasis. Microglia are currently considered to be the major phagocytes in... (Review)
Review
Phagocytosis by glial cells has been shown to play an important role in maintaining brain homeostasis. Microglia are currently considered to be the major phagocytes in the brain parenchyma, and these cells phagocytose a variety of materials, including dead cell debris, abnormally aggregated proteins, and, interestingly, the functional synapses of living neurons. The intracellular signaling mechanisms that regulate microglial phagocytosis have been studied extensively, and several important factors, including molecules known as "find me" signals and "eat me" signals and receptors on microglia that are involved in phagocytosis, have been identified. In addition, recent studies have revealed that astrocytes, which are another major glial cell in the brain parenchyma, also have phagocytic abilities. In this review, we will discuss the roles of microglia and astrocytes in phagocytosis-mediated brain homeostasis, focusing on the characteristics and differences of their phagocytic abilities.
Topics: Animals; Astrocytes; Brain; Homeostasis; Humans; Neuroglia; Neurons; Phagocytes
PubMed: 34072424
DOI: 10.3390/cells10061348 -
Methods in Molecular Biology (Clifton,... 2018Macrophages are a heterogeneous population of innate immune cells and are distributed in most adult tissues. Certain tissue-resident macrophages with a prenatal origin,... (Review)
Review
Macrophages are a heterogeneous population of innate immune cells and are distributed in most adult tissues. Certain tissue-resident macrophages with a prenatal origin, together with postnatal monocyte-derived macrophages, serve as the host scavenger system to eliminate invading pathogens, malignant cells, senescent cells, dead cells, cellular debris, and other foreign substances. As a key member of the mononuclear phagocyte system, macrophages play essential roles in regulation of prenatal development, tissue homeostasis, and disease progression. Over the past two decades, considerable efforts have been made to generate genetic models of macrophage ablation in mice. These models support investigations of the precise functions of tissue-specific macrophages under physiological and pathological conditions. Herein, we overview the currently available mouse strains for in vivo genetic ablation of macrophages and discuss their respective advantages and limitations.
Topics: Animals; Cell Lineage; Disease Models, Animal; Humans; Macrophages; Mice; Models, Genetic; Organ Specificity; Phagocytes; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
PubMed: 29761404
DOI: 10.1007/978-1-4939-7837-3_22