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Archives of Microbiology Nov 2023Efferocytosis is characterized as the rapid and efficient process by which dying or dead cells are removed. This type of clearance is initiated via "find-me" signals,... (Review)
Review
Efferocytosis is characterized as the rapid and efficient process by which dying or dead cells are removed. This type of clearance is initiated via "find-me" signals, and then, carries on by "eat-me" and "don't-eat-me" ones. Efferocytosis has a critical role to play in tissue homeostasis and innate immunity. However, some evidence suggests it as a double-edged sword in microbial immunity. In other words, some pathogens have degraded efferocytosis by employing efferocytic mechanisms to bypass innate immune detection and promote infection, despite the function of this process for the control and clearance of pathogens. In this review, the efferocytosis mechanisms from the recognition of dying cells to phagocytic engulfment are initially presented, and then, its diverse roles in inflammation and immunity are highlighted. In this case, much focus is also laid on some bacterial, viral, and parasitic infections caused by Mycobacterium tuberculosis (M. tb), Mycobacterium marinum (M. marinum), Listeria monocytogenes (L. monocytogenes), Chlamydia pneumoniae (CP), Klebsiella pneumoniae (KP), Influenza A virus (IAV), human immunodeficiency virus (HIV), and Leishmania, respectively.
Topics: Humans; Macrophages; Phagocytosis; Immunity, Innate; Inflammation; Mycobacterium tuberculosis; Apoptosis
PubMed: 37925389
DOI: 10.1007/s00203-023-03704-8 -
Cellular & Molecular Immunology Sep 2023Neutrophils, as the first defenders against external microbes and stimuli, are highly active and finely regulated innate immune cells. Emerging evidence has challenged... (Review)
Review
Neutrophils, as the first defenders against external microbes and stimuli, are highly active and finely regulated innate immune cells. Emerging evidence has challenged the conventional dogma that neutrophils are a homogeneous population with a short lifespan that promotes tissue damage. Recent findings on neutrophil diversity and plasticity in homeostatic and disease states have centered on neutrophils in the circulation. In contrast, a comprehensive understanding of tissue-specialized neutrophils in health and disease is still lacking. This article will first discuss how multiomics advances have contributed to our understanding of neutrophil heterogeneity and diversification in resting and pathological settings. This discussion will be followed by a focus on the heterogeneity and role of neutrophils in solid organ transplantation and how neutrophils may contribute to transplant-related complications. The goal of this article is to provide an overview of the research on the involvement of neutrophils in transplantation, with the aim that this may draw attention to an underappreciated area of neutrophil research.
Topics: Neutrophils; Organ Transplantation
PubMed: 37386174
DOI: 10.1038/s41423-023-01058-1 -
Molecular Neurodegeneration Aug 2023Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral...
Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer's disease mice.
BACKGROUND
Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-β (Aβ) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, further investigations are required to understand how perivascular macrophages play a role in enhancing CAA-related vascular permeability and microhemorrhages associated with amyloid immunotherapy.
METHODS
In this study, we examined immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using histology and gene expression analyses in Alzheimer's disease (AD) mouse models and primary culture systems.
RESULTS
In the present study, we demonstrate that anti-Aβ (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169 perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aβ immunotherapy.
CONCLUSIONS
In summary, our study establishes a connection between Aβ antibodies engaged at CAA deposits, the activation of perivascular macrophages, and the upregulation of genes involved in vascular permeability. However, the implications of this phenomenon on the susceptibility to microhemorrhages remain to be fully elucidated. Further investigations are warranted to determine the precise role of CD169 + perivascular macrophages in enhancing CAA-mediated vascular permeability, extravasation of plasma proteins, and infiltration of immune cells associated with microhemorrhages.
Topics: Animals; Mice; Alzheimer Disease; Monocytes; Plaque, Amyloid; Amyloid beta-Peptides; Cerebral Amyloid Angiopathy; Macrophages; Amyloidogenic Proteins
PubMed: 37649100
DOI: 10.1186/s13024-023-00649-w -
Cell Death & Disease Aug 2023Liver regeneration is a dynamic and regulated process that involves inflammation, granulation, and tissue remodeling. Hepatic macrophages, abundantly distributed in the... (Review)
Review
Liver regeneration is a dynamic and regulated process that involves inflammation, granulation, and tissue remodeling. Hepatic macrophages, abundantly distributed in the liver, are essential components that actively participate in each step to orchestrate liver regeneration. In the homeostatic liver, resident macrophages (Kupffer cells) acquire a tolerogenic phenotype and contribute to immunological tolerance. Following toxicity-induced damage or physical resection, Kupffer cells as well as monocyte-derived macrophages can be activated and promote an inflammatory process that supports the survival and activation of hepatic myofibroblasts and thus promotes scar tissue formation. Subsequently, these macrophages, in turn, exhibit the anti-inflammatory effects critical to extracellular matrix remodeling during the resolution stage. However, continuous damage-induced chronic inflammation generally leads to hepatic macrophage dysfunction, which exacerbates hepatocellular injury and triggers further liver fibrosis and even cirrhosis. Emerging macrophage-targeting strategies have shown efficacy in both preclinical and clinical studies. Increasing evidence indicates that metabolic rewiring provides substrates for epigenetic modification, which endows monocytes/macrophages with prolonged "innate immune memory". Therefore, it is reasonable to conceive novel therapeutic strategies for metabolically reprogramming macrophages and thus mediate a homeostatic or reparative process for hepatic inflammation management and liver regeneration.
Topics: Humans; Kupffer Cells; Liver Regeneration; Macrophages; Homeostasis; Liver Cirrhosis; Inflammation
PubMed: 37644019
DOI: 10.1038/s41419-023-06066-7 -
Molecular Biology Reports Aug 2023Atherosclerosis (AS) is the leading cause of the human cardiovascular diseases (CVDs). Endothelial dysfunction promotes the monocytes infiltration and inflammation that... (Review)
Review
Atherosclerosis (AS) is the leading cause of the human cardiovascular diseases (CVDs). Endothelial dysfunction promotes the monocytes infiltration and inflammation that participate fundamentally in atherogenesis. Endothelial cells (EC) have been recognized as mechanosensitive cells and have different responses to distinct mechanical stimuli. Emerging evidence shows matrix stiffness-mediated EC dysfunction plays a vital role in vascular disease, but the underlying mechanisms are not yet completely understood. This article aims to summarize the effect of matrix stiffness on the pro-atherosclerotic characteristics of EC including morphology, rigidity, biological behavior and function as well as the related mechanical signal. The review also discusses and compares the contribution of matrix stiffness-mediated phagocytosis of macrophages and EC to AS progression. These advances in our understanding of the relationship between matrix stiffness and EC dysfunction open the avenues to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases.
Topics: Humans; Endothelial Cells; Signal Transduction; Atherosclerosis; Macrophages; Monocytes
PubMed: 37382775
DOI: 10.1007/s11033-023-08502-5 -
Experimental & Molecular Medicine Aug 2023Cells constituting a multicellular organism die in a variety of ways throughout life, and most of them die via apoptosis under normal conditions. The occurrence of... (Review)
Review
Cells constituting a multicellular organism die in a variety of ways throughout life, and most of them die via apoptosis under normal conditions. The occurrence of apoptosis is especially prevalent during development and in tissues with a high cellular turnover rate, such as the thymus and bone marrow. Interestingly, although the number of apoptotic cells produced daily is known to be innumerable in a healthy adult human body, apoptotic cells are rarely observed. This absence is due to the existence of a cellular process called efferocytosis that efficiently clears apoptotic cells. Studies over the past decades have focused on how phagocytes are able to remove apoptotic cells specifically, swiftly, and continuously, resulting in defined molecular and cellular events. In this review, we will discuss the current understanding of the clearance of apoptotic cells at the molecular level.
Topics: Adult; Humans; Cell Death; Phagocytosis; Apoptosis; Phagocytes; Kinetics
PubMed: 37612408
DOI: 10.1038/s12276-023-01070-5 -
Carbohydrate Polymers May 2024Glucan is a natural polysaccharide widely distributed in cereals and microorganisms that has various biological activities, including immunomodulatory, anti-infective,... (Review)
Review
Glucan is a natural polysaccharide widely distributed in cereals and microorganisms that has various biological activities, including immunomodulatory, anti-infective, anti-inflammatory, and antitumor activities. In addition to wide applications in the broad fields of food, healthcare, and biomedicines, glucans hold promising potential as drug delivery carrier materials or ligands. Specifically, glucan microparticles or yeast cell wall particles are naturally enclosed vehicles with an interior cavity that can be exploited to carry and deliver drug payloads. The biological activities and targeting capacities of glucans depend largely on the recognition of glucan moieties by receptors such as dectin-1 and complement receptor 3, which are widely expressed on the cell membranes of mononuclear phagocytes, dendritic cells, neutrophils, and some lymphocytes. This review summarizes the chemical structures, sources, fundamental properties, extraction methods, and applications of these materials, with an emphasis on drug delivery. Glucans are utilized mainly as vaccine adjuvants, targeting ligands and as carrier materials for various drug entities. It is believed that glucans and glucan microparticles may be useful for the delivery of both small-molecule and macromolecular drugs, especially for potential treatment of immune-related diseases.
Topics: Glucans; beta-Glucans; Saccharomyces cerevisiae; Neutrophils; Carrier Proteins; Lectins, C-Type
PubMed: 38431411
DOI: 10.1016/j.carbpol.2024.121904 -
Nature Communications Sep 2023GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely...
GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-G signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual G-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
Topics: Phagocytes; Signal Transduction; Macrophages; Phagocytosis; Fatty Acids
PubMed: 37709767
DOI: 10.1038/s41467-023-41201-0 -
Progress in Lipid Research Nov 2023Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various... (Review)
Review
Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various particles, including lipids. Defective lipid handling can drive excessive lipid accumulation leading to foam cell formation, a key feature of various cardiometabolic conditions such as atherosclerosis, non-alcoholic fatty liver disease, and obesity. At the same time, intracellular lipid storage and foam cell formation can also be viewed as a protective and anti-lipotoxic mechanism against a lipid-rich environment and associated elevated lipid uptake. Traditionally, foam cell formation has primarily been linked to cholesterol uptake via native and modified low-density lipoproteins. However, other lipids, including non-esterified fatty acids and triacylglycerol (TAG)-rich lipoproteins (very low-density lipoproteins and chylomicrons), can also interact with macrophages. Recent studies have identified multiple pathways mediating TAG uptake and processing by macrophages, including endocytosis and receptor/transporter-mediated internalization and transport. This review will present the current knowledge of how macrophages take up different lipids and lipoprotein particles and address how TAG-rich lipoproteins are processed intracellularly. Understanding how macrophages take up and process different lipid species such as TAG is necessary to design future therapeutic interventions to correct excessive lipid accumulation and associated co-morbidities.
Topics: Triglycerides; Fatty Acids; Macrophages; Lipoproteins; Foam Cells; Lipoproteins, LDL
PubMed: 37619883
DOI: 10.1016/j.plipres.2023.101250