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Journal of Leukocyte Biology Sep 2019Leukocytes are a large population of cells spread within most tissues in the body. These cells may be either sessile (called as resident cells) or circulating... (Review)
Review
Leukocytes are a large population of cells spread within most tissues in the body. These cells may be either sessile (called as resident cells) or circulating leukocytes, which travel long journeys inside the vessels during their lifespan. Although production and maturation of these leukocytes in adults primarily occur in the bone marrow, it is well known that this process-called hematopoiesis-started in the embryonic life in different sites, including the yolk sac, placenta, and the liver. In this review, we will discuss how the liver acts as a pivotal site for leukocyte maturation during the embryo phase, and also how the most frequent liver-resident immune cell populations-namely Kupffer cells, dendritic cells, and lymphocytes-play a vital role in both tolerance and inflammatory responses to antigens from food, microbiota, and pathogens.
Topics: Animals; Cell Lineage; Hematopoiesis; Humans; Leukocytes; Liver; Phagocytes
PubMed: 31107980
DOI: 10.1002/JLB.MR1118-455R -
Advances in Experimental Medicine and... 2020The key purpose of phagocytosis is the destruction of pathogenic microorganisms. The phagocytes exert a wide array of killing mechanisms that allow mastering the vast... (Review)
Review
The key purpose of phagocytosis is the destruction of pathogenic microorganisms. The phagocytes exert a wide array of killing mechanisms that allow mastering the vast majority of pathogens. One of these mechanisms consists in the production of reactive oxygen species inside the phagosome by a specific enzyme, the phagocyte NADPH oxidase. This enzyme is composed of 6 proteins that need to assemble to form a complex on the phagosomal membrane. Multiple signaling pathways tightly regulate the assembly. We briefly summarize key features of the enzyme and its regulation. We then focus on several related topics that address the activity of the NADPH oxidase during phagocytosis. Novel fluorescence microscopy techniques combined with fluorescent protein labeling of NADPH oxidase subunits opened the view on the structure and dynamics of these proteins in living cells. This combination revealed details of the role of anionic phospholipids in the control of phagosomal ROS production. It also added critical information to propose a 3D model of the complex between the cytosolic subunits prior to activation, in complement to other structural data on the oxidase.
Topics: Humans; NADPH Oxidases; Phagocytes; Phagocytosis; Phagosomes; Reactive Oxygen Species
PubMed: 32399830
DOI: 10.1007/978-3-030-40406-2_9 -
Frontiers in Immunology 2023Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens,... (Review)
Review
Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens, pathogen components, and non-infectious particles. However, tissue injury-related changes in local microenvironments activate resident and infiltrating MP towards pro-inflammatory phenotypes that contribute to inflammation by secreting additional inflammatory mediators. Efficient control of injurious factors leads to a switch of MP phenotype, which changes the microenvironment towards the resolution of inflammation. In the same way, MP endorses adaptive structural responses leading to either compensatory hypertrophy of surviving cells, tissue regeneration from local tissue progenitor cells, or tissue fibrosis and atrophy. Under certain circumstances, MP contribute to the reversal of tissue fibrosis by clearance of the extracellular matrix. Here we give an update on the tissue microenvironment-related factors that, upon tissue injury, instruct resident and infiltrating MP how to support host defense and recover tissue function and integrity. We propose that MP are not intrinsically active drivers of organ injury and dysfunction but dynamic amplifiers (and biomarkers) of specific tissue microenvironments that vary across spatial and temporal contexts. Therefore, MP receptors are frequently redundant and suboptimal targets for specific therapeutic interventions compared to molecular targets upstream in adaptive humoral or cellular stress response pathways that influence tissue milieus at a contextual level.
Topics: Humans; Macrophages; Monocytes; Fibrosis; Inflammation; Atrophy
PubMed: 37868987
DOI: 10.3389/fimmu.2023.1194988 -
Redox Biology Aug 2023Reactive oxygen species (ROS) are a family of highly reactive molecules with numerous, often pleiotropic functions within the cell and the organism. Due to their... (Review)
Review
Reactive oxygen species (ROS) are a family of highly reactive molecules with numerous, often pleiotropic functions within the cell and the organism. Due to their potential to destroy biological structures such as membranes, enzymes and organelles, ROS have long been recognized as harmful yet unavoidable by-products of cellular metabolism leading to "oxidative stress" unless counterbalanced by cellular anti-oxidative defense mechanisms. Phagocytes utilize this destructive potential of ROS released in high amounts to defend against invading pathogens. In contrast, a regulated and fine-tuned release of "signaling ROS" (sROS) provides essential intracellular second messengers to modulate central aspects of immunity, including antigen presentation, activation of antigen presenting cells (APC) as well as the APC:T cell interaction during T cell activation. This regulated release of sROS is foremost attributed to the specialized enzyme NADPH-oxidase (NOX) 2 expressed mainly in myeloid cells such as neutrophils, macrophages and dendritic cells (DC). NOX-2-derived sROS are primarily involved in immune regulation and mediate protection against autoimmunity as well as maintenance of self-tolerance. Consequently, deficiencies in NOX2 not only result in primary immune-deficiencies such as Chronic Granulomatous Disease (CGD) but also lead to auto-inflammatory diseases and autoimmunity. A comprehensive understanding of NOX2 activation and regulation will be key for successful pharmaceutical interventions of such ROS-related diseases in the future. In this review, we summarize recent progress regarding immune regulation by NOX2-derived ROS and the consequences of its deregulation on the development of immune disorders.
Topics: Humans; Reactive Oxygen Species; NADPH Oxidases; Neutrophils; Granulomatous Disease, Chronic; Phagocytes
PubMed: 37379662
DOI: 10.1016/j.redox.2023.102795 -
Immunological Reviews Mar 2023Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating... (Review)
Review
Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole-like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived antimicrobial agents and granule-delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate.
Topics: Humans; Neutrophils; Phagosomes; Phagocytosis; Phagocytes; Reactive Oxygen Species
PubMed: 36440666
DOI: 10.1111/imr.13173 -
Frontiers in Endocrinology 2020Atherosclerosis (AS) is the main pathological basis for the development of cardio-cerebrovascular diseases. Abnormal accumulation of apoptotic and necrotic cells... (Review)
Review
Atherosclerosis (AS) is the main pathological basis for the development of cardio-cerebrovascular diseases. Abnormal accumulation of apoptotic and necrotic cells resulted in plaque enlargement, necrotic core formation and plaque rupture in AS. Under physiological conditions, apoptotic cells (ACs) could be effectively phagocytized and cleared by phagocyte-mediated efferocytosis. In contrast, the clearance efficiency of ACs in AS plaque was much lower because of the impaired efferocytosis in AS. Recent findings have made great progress on the molecular mechanisms of efferocytosis process and dynamic regulation, and its dysfunction on organismal health. Yet, there are still few effective treatments for this process. This article reviews the mechanism of efferocytosis and the role of efferocytosis in AS, highlighting a novel therapeutic strategy for AS, which mainly prevents the progression of plaque by targeting efferocytosis.
Topics: Animals; Apoptosis; Atherosclerosis; Humans; Necrosis; Phagocytes; Phagocytosis
PubMed: 33597922
DOI: 10.3389/fendo.2020.585285 -
Frontiers in Endocrinology 2021Endogenous oxidized phospholipids are produced during tissue stress and are responsible for sustaining inflammatory responses in immune as well as non-immune cells.... (Review)
Review
Endogenous oxidized phospholipids are produced during tissue stress and are responsible for sustaining inflammatory responses in immune as well as non-immune cells. Their local and systemic production and accumulation is associated with the etiology and progression of several inflammatory diseases, but the molecular mechanisms that underlie the biological activities of these oxidized phospholipids remain elusive. Increasing evidence highlights the ability of these stress mediators to modulate cellular metabolism and pro-inflammatory signaling in phagocytes, such as macrophages and dendritic cells, and to alter the activation and polarization of these cells. Because these immune cells serve a key role in maintaining tissue homeostasis and organ function, understanding how endogenous oxidized lipids reshape phagocyte biology and function is vital for designing clinical tools and interventions for preventing, slowing down, or resolving chronic inflammatory disorders that are driven by phagocyte dysfunction. Here, we discuss the metabolic and signaling processes elicited by endogenous oxidized lipids and outline new hypotheses and models to elucidate the impact of these lipids on phagocytes and inflammation.
Topics: Animals; COVID-19; Humans; Inflammation; Oxidation-Reduction; Phagocytes; Phospholipids
PubMed: 33790857
DOI: 10.3389/fendo.2021.626842 -
Nature Communications Sep 2022We have recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting,...
We have recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting, immunosuppressive B cells. Here, using various murine tumor models and samples from humans with breast and ovarian cancers, we provide evidence that cancers also co-opt differentiation of these B-cell precursors to generate macrophage-like cells (termed B-MF). We link the transdifferentiation to a small subset of CSF1R Pax5 cells within BM pre-B and immature B cells responding to cancer-secreted M-CSF with downregulation of the transcription factor Pax5 via CSF1R signaling. Although the primary source of tumor-associated macrophages is monocytes, B-MFs are phenotypically and functionally distinguishable. Compared to monocyte-derived macrophages, B-MFs more efficiently phagocytize apoptotic cells, suppress proliferation of T cells and induce FoxP3 regulatory T cells. In mouse tumor models, B-MFs promote shrinkage of the tumor-infiltrating IFNγ CD4 T cell pool and increase cancer progression and metastasis, suggesting that this cancer-induced transdifferentiation pathway is functionally relevant and hence could serve as an immunotherapeutic target.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Humans; Macrophages; Mice; Monocytes; Neoplasms
PubMed: 36104343
DOI: 10.1038/s41467-022-33117-y -
The Journal of Clinical Investigation Dec 2019Resolution of acute inflammation is an active process orchestrated by endogenous mediators and mechanisms pivotal in host defense and homeostasis. The macrophage...
Resolution of acute inflammation is an active process orchestrated by endogenous mediators and mechanisms pivotal in host defense and homeostasis. The macrophage mediator in resolving inflammation, maresin 1 (MaR1), is a potent immunoresolvent, stimulating resolution of acute inflammation and organ protection. Using an unbiased screening of greater than 200 GPCRs, we identified MaR1 as a stereoselective activator for human leucine-rich repeat containing G protein-coupled receptor 6 (LGR6), expressed in phagocytes. MaR1 specificity for recombinant human LGR6 activation was established using reporter cells expressing LGR6 and functional impedance sensing. MaR1-specific binding to LGR6 was confirmed using 3H-labeled MaR1. With human and mouse phagocytes, MaR1 (0.01-10 nM) enhanced phagocytosis, efferocytosis, and phosphorylation of a panel of proteins including the ERK and cAMP response element-binding protein. These MaR1 actions were significantly amplified with LGR6 overexpression and diminished by gene silencing in phagocytes. Thus, we provide evidence for MaR1 as an endogenous activator of human LGR6 and a novel role of LGR6 in stimulating MaR1's key proresolving functions of phagocytes.
Topics: Animals; Docosahexaenoic Acids; Extracellular Signal-Regulated MAP Kinases; Gene Silencing; HEK293 Cells; Humans; Inflammation; Macrophages; Mice; Phagocytes; Phagocytosis; Phosphorylation; RNA, Small Interfering; Receptors, G-Protein-Coupled; THP-1 Cells
PubMed: 31657786
DOI: 10.1172/JCI129448 -
Trends in Endocrinology and Metabolism:... Sep 2019There is evidence of the critical role of efferocytosis, the clearance of apoptotic cells (ACs) by phagocytes, in vascular cell homeostasis and protection against... (Review)
Review
There is evidence of the critical role of efferocytosis, the clearance of apoptotic cells (ACs) by phagocytes, in vascular cell homeostasis and protection against atherosclerosis. Specific microRNAs (miRs) can regulate atherogenesis by controlling the accumulation of professional phagocytes (e.g., macrophages) and nonprofessional phagocytes (i.e., neighboring tissue cells with the ability to acquire a macrophage-like phenotype) within the arterial wall, the differentiation of phagocytes into foam cells, the efferocytosis of apoptotic foam cells by phagocytes, and the phagocyte-mediated inflammatory response. A better understanding of the mechanisms involved in miR-regulated phagocyte function might lead to novel therapeutic antiatherosclerotic strategies. In this review, we try to shed light on the relationship between miRs and cellular players in the process of efferocytosis in the context of atherosclerotic plaque and their potential as molecular targets for novel antiatherosclerotic therapies.
Topics: Animals; Apoptosis; Atherosclerosis; Humans; Macrophages; MicroRNAs
PubMed: 31383556
DOI: 10.1016/j.tem.2019.07.006