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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 -
Current Opinion in Cell Biology Aug 2022Cells ingest large particles, such as bacteria, viruses, or apoptotic cells, via the process of phagocytosis, which involves formation of an actin-rich structure known... (Review)
Review
Cells ingest large particles, such as bacteria, viruses, or apoptotic cells, via the process of phagocytosis, which involves formation of an actin-rich structure known as the phagocytic cup. Phagocytic cup assembly and closure results from a concerted action of phagocytic receptors, regulators of actin polymerization, and myosin motors. Recent studies using advanced imaging approaches and biophysical techniques have revealed new information regarding phagocytic cup architecture, regulation of actin assembly, and the distribution, direction, and magnitude of the forces produced by the cytoskeletal elements that form the cup. These findings provide insights into the mechanisms leading to the assembly, expansion, and closure of phagocytic cups. The new data show that engulfment and internalization of phagocytic targets rely on several distinct yet complementary mechanisms that support the robust uptake of foreign objects and may be precisely tailored to the demands of specific phagocytic pathways.
Topics: Actins; Cell Membrane; Cytoskeleton; Phagocytes; Phagocytosis
PubMed: 35820329
DOI: 10.1016/j.ceb.2022.102112 -
ACS Nano Jul 2020Mononuclear phagocytes such as monocytes, tissue-specific macrophages, and dendritic cells are primary actors in both innate and adaptive immunity. These professional...
Mononuclear phagocytes such as monocytes, tissue-specific macrophages, and dendritic cells are primary actors in both innate and adaptive immunity. These professional phagocytes can be parasitized by intracellular bacteria, turning them from housekeepers to hiding places and favoring chronic and/or disseminated infection. One of the most infamous is the bacteria that cause tuberculosis (TB), which is the most pandemic and one of the deadliest diseases, with one-third of the world's population infected and an average of 1.8 million deaths/year worldwide. Here we demonstrate the effective targeting and intracellular delivery of antibiotics to infected macrophages both and , using pH-sensitive nanoscopic polymersomes made of PMPC-PDPA block copolymer. Polymersomes showed the ability to significantly enhance the efficacy of the antibiotics killing , , and another established intracellular pathogen, . Moreover, they demonstrated to easily access TB-like granuloma tissues-one of the harshest environments to penetrate-in zebrafish models. We thus successfully exploited this targeting for the effective eradication of several intracellular bacteria, including , the etiological agent of human TB.
Topics: Animals; Humans; Macrophages; Monocytes; Mycobacterium tuberculosis; Tuberculosis; Zebrafish
PubMed: 32515944
DOI: 10.1021/acsnano.0c01870 -
DNA and Cell Biology Feb 2021Effective and efficient efferocytosis of dead cells and associated cellular debris are critical to tissue homeostasis and healing of injured tissues. This important task... (Review)
Review
Effective and efficient efferocytosis of dead cells and associated cellular debris are critical to tissue homeostasis and healing of injured tissues. This important task was previously thought to be restricted to professional phagocytes (PPs). However, accumulating evidence has revealed another type of phagocyte, the amateur phagocyte (AP), which can also participate in efferocytosis. APs are non-myeloid progenitor/nonimmune cells that include differentiated cells (e.g., epithelial cells, fibroblasts, and endothelial cells [ECs]) and stem cells (e.g., neuronal progenitor cells and mesenchymal cells) and can be found throughout the human body. Studies have shown that APs have two prominent roles: identifying and removing dead cells presumably before PPs reach the site of injury and assisting PPs in the removal of cell corpses and the resolution of inflamed tissue. With respect to the engulfment and degradation of dead cells, APs are slower and less efficient than PPs. However, APs are fundamental to preventing the spread of inflammation over a large area. In this review, we present the diversity and characteristics of healthy and non-neoplastic APs in mammals. We also propose a hypothetical mechanism of the efferocytosis of immunoglobulin G (IgG)-opsonized myelin debris by ECs (APs). Furthermore, the ingestion and clearance of dead cells can induce proinflammatory or anti-inflammatory cytokine production, endothelial activation, and cellular fate transition, which contribute to the progression of disease. An understanding of the role of APs is necessary to develop effective intervention strategies, including potential molecular targets for clinical diagnosis and drug development, for inflammation-related diseases.
Topics: Animals; Humans; Phagocytes
PubMed: 33439750
DOI: 10.1089/dna.2020.5647 -
Frontiers in Immunology 2022Resident macrophages play a unique role in the maintenance of tissue function. As phagocytes, they are an essential first line defenders against pathogens and much of... (Review)
Review
Resident macrophages play a unique role in the maintenance of tissue function. As phagocytes, they are an essential first line defenders against pathogens and much of the initial characterization of these cells was focused on their interaction with viral and bacterial pathogens. However, these cells are increasingly recognized as contributing to more than just host defense. Through cytokine production, receptor engagement and gap junction communication resident macrophages tune tissue inflammatory tone, influence adaptive immune cell phenotype and regulate tissue structure and function. This review highlights resident macrophages in the liver and lung as they hold unique roles in the maintenance of the interface between the circulatory system and the external environment. As such, we detail the developmental origin of these cells, their contribution to host defense and the array of tools these cells use to regulate tissue homeostasis.
Topics: Macrophages; Liver; Lung; Phagocytes; Homeostasis
PubMed: 36532044
DOI: 10.3389/fimmu.2022.1029085 -
Proceedings of the National Academy of... Sep 2023A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of...
A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of phagocytes that play a key role in lesion progression and remyelination, and therefore represent a promising therapeutic target in MS. We recently showed that unsaturated fatty acids produced by stearoyl-CoA desaturase-1 induce inflammatory foam cell formation during demyelination. These fatty acids are elongated by the "elongation of very long chain fatty acids" proteins (ELOVLs), generating a series of functionally distinct lipids. Here, we show that the expression and activity of ELOVLs are altered in myelin-induced foam cells. Especially ELOVL6, an enzyme responsible for converting saturated and monounsaturated C16 fatty acids into C18 species, was found to be up-regulated in myelin phagocytosing phagocytes in vitro and in MS lesions. Depletion of induced a repair-promoting phagocyte phenotype through activation of the S1P/PPARγ pathway. -deficient foamy macrophages showed enhanced ABCA1-mediated lipid efflux, increased production of neurotrophic factors, and reduced expression of inflammatory mediators. Moreover, our data show that ELOVL6 hampers CNS repair, as deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the mouse cuprizone model. These findings indicate that targeting ELOVL6 activity may be an effective strategy to stimulate CNS repair in MS and other neurodegenerative diseases.
Topics: Animals; Mice; Adipogenesis; Disease Models, Animal; Fatty Acids; Fatty Acids, Monounsaturated; Foam Cells; Multiple Sclerosis; Remyelination
PubMed: 37669365
DOI: 10.1073/pnas.2301030120 -
Glia Jun 2022Elimination of dead or live cells take place in both a healthy and diseased central nervous system (CNS). Dying or dead cells are quickly cleared by phagocytosis for the... (Review)
Review
Elimination of dead or live cells take place in both a healthy and diseased central nervous system (CNS). Dying or dead cells are quickly cleared by phagocytosis for the maintenance of a healthy CNS or for recovery after injury. Live cells or parts thereof, such as the synapses and myelin, are appropriately eliminated by phagocytosis to maintain or refine neural networks during development and adulthood. Microglia, the specific population of resident macrophages in the CNS, are classically considered as primary phagocytes; however, astrocytes have also been highlighted as phagocytes in the last decade. Phagocytic targets and receptors are reported to be mostly common between astrocytes and microglia, which raises the question of how astrocytic phagocytosis differs from microglial phagocytosis, and how these two phagocytic systems cooperate. In this review, we address the consequences of astrocytic phagocytosis, particularly focusing on these elusive points.
Topics: Astrocytes; Central Nervous System; Microglia; Phagocytes; Phagocytosis
PubMed: 35142399
DOI: 10.1002/glia.24145