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Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.The Journal of Experimental Medicine Jun 2023Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear....
Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.
Topics: Humans; Macrophages; Phagocytosis; Lung Neoplasms; Myeloid Cells; Oxidative Stress; Tumor Microenvironment
PubMed: 36995340
DOI: 10.1084/jem.20221472 -
Seminars in Immunology Nov 2023Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed... (Review)
Review
Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation.
Topics: Humans; Neutrophils; Pyroptosis; Phagocytosis; Apoptosis
PubMed: 37939552
DOI: 10.1016/j.smim.2023.101849 -
Nature Communications Oct 2022Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely...
Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia are removed. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization. The engulfed microglial fragments are then degraded in astrocytes via RUBICON-dependent LC3-associated phagocytosis (LAP), a form of noncanonical autophagy. Interference with C4b-mediated engulfment and subsequent LAP disrupt the removal and degradation of microglial debris, respectively. Together, we elucidate the cellular and molecular mechanisms of microglial debris removal in mice, extending the knowledge on the maintenance of CNS homeostasis.
Topics: Animals; Mice; Microglia; Astrocytes; Phagocytosis; Autophagy; Central Nervous System; Intracellular Signaling Peptides and Proteins
PubMed: 36280666
DOI: 10.1038/s41467-022-33932-3 -
Cell Reports Jul 2023Tissue-resident macrophages (TRMs) and dendritic cells (DCs) are highly heterogeneous and essential for immunity, tissue regeneration, and homeostasis maintenance. Here,...
Tissue-resident macrophages (TRMs) and dendritic cells (DCs) are highly heterogeneous and essential for immunity, tissue regeneration, and homeostasis maintenance. Here, we comprehensively profile the heterogeneity of TRMs and DCs across adult zebrafish organs via single-cell RNA sequencing. We identify two macrophage subsets: pro-inflammatory macrophages with potent phagocytosis signatures and pro-remodeling macrophages with tissue regeneration signatures in barrier tissues, liver, and heart. In parallel, one conventional dendritic cell (cDC) population with prominent antigen presentation capacity and plasmacytoid dendritic cells (pDCs) featured by anti-virus properties are also observed in these organs. Remarkably, in addition to a single macrophage/microglia population with potent phagocytosis capacity, a pDC population and two distinct cDC populations are identified in the brain. Finally, we generate specific reporter lines for in vivo tracking of macrophage and DC subsets. Our study depicts the landscape of TRMs and DCs and creates valuable tools for in-depth study of these cells in zebrafish.
Topics: Animals; Zebrafish; Macrophages; Gene Expression Profiling; Dendritic Cells; Phagocytosis; Transcriptome
PubMed: 37453064
DOI: 10.1016/j.celrep.2023.112793 -
Frontiers in Immunology 2020
Topics: Animals; Humans; Phagocytosis
PubMed: 33072133
DOI: 10.3389/fimmu.2020.586918 -
Immunity Dec 2022Microglia utilize their phagocytic activity to prune redundant synapses and refine neural circuits during precise developmental periods. However, the neuronal signals...
Microglia utilize their phagocytic activity to prune redundant synapses and refine neural circuits during precise developmental periods. However, the neuronal signals that control this phagocytic clockwork remain largely undefined. Here, we show that neuronal signal-regulatory protein alpha (SIRPα) is a permissive cue for microglial phagocytosis in the developing murine retina. Removal of neuronal, but not microglial, SIRPα reduced microglial phagocytosis, increased synpase numbers, and impaired circuit function. Conversely, prolonging neuronal SIRPα expression extended developmental microglial phagocytosis. These outcomes depended on the interaction of presynaptic SIRPα with postsynaptic CD47. Global CD47 deficiency modestly increased microglial phagocytosis, while CD47 overexpression reduced it. This effect was rescued by coexpression of neuronal SIRPα or codeletion of neuronal SIRPα and CD47. These data indicate that neuronal SIRPα regulates microglial phagocytosis by limiting microglial SIRPα access to neuronal CD47. This discovery may aid our understanding of synapse loss in neurological diseases.
Topics: Mice; Animals; CD47 Antigen; Receptors, Immunologic; Macrophages; Phagocytosis; Retina; Antigens, Differentiation
PubMed: 36379210
DOI: 10.1016/j.immuni.2022.10.018 -
Advances in Experimental Medicine and... 2020Phagocytosis is usually defined as the cellular process by which cells internalise particulate matter larger than about 0.5 μm in diameter. It is an endocytic process,... (Review)
Review
Phagocytosis is usually defined as the cellular process by which cells internalise particulate matter larger than about 0.5 μm in diameter. It is an endocytic process, distinct from pinocytosis and macropinocytosis. These latter processes may internalise small particles suspended the extracellular fluid, but this is a by-product of internalising the fluid, and is not phagocytosis per se. In contrast, phagocytosis is targeted at solid particulates, usually microbes, which are internalised and "digested" either to provide food, or as part of the immune system of higher animals. The mechanism of phagocytosis may have, at its core, many primitive elements, but it is a highly complex and coordinated series of cell biological and molecular events which together result in the uptake of a particle. In this introduction, the basis of phagocytosis and some ideas of its origin are discussed.
Topics: Animals; Phagocytosis
PubMed: 32399822
DOI: 10.1007/978-3-030-40406-2_1 -
Nature Cancer Apr 2022Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the...
Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.
Topics: Cytophagocytosis; Cytoskeletal Proteins; Glutamine; Humans; Macrophages; Mitochondrial Dynamics; Neoplasms; Phagocytosis; Protein Kinase C-theta; Wiskott-Aldrich Syndrome Protein
PubMed: 35484420
DOI: 10.1038/s43018-022-00354-5 -
Frontiers in Cellular and Infection... 2022Sepsis is associated with a high risk of death, and the crosstalk between gut microbiota and sepsis is gradually revealed. Indole 3-propionic acid (IPA) is a gut...
Sepsis is associated with a high risk of death, and the crosstalk between gut microbiota and sepsis is gradually revealed. Indole 3-propionic acid (IPA) is a gut microbiota-derived metabolite that exerts immune regulation and organ protective effects. However, the role of IPA in sepsis is not clear. In this study, the role of IPA in sepsis-related survival, clinical scores, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Aryl hydrocarbon receptor (AhR) highly specific inhibitor (CH223191) was used to observe the role of AhR in the protection of IPA against sepsis. The effects of IPA on bacterial phagocytosis by macrophages were investigated and vitro. The levels of IPA in feces were measured and analyzed in human sepsis patients and patient controls. First, we found that gut microbiota-derived IPA was associated with the survival of septic mice. Then, in animal model, IPA administration protected against sepsis-related mortality and alleviated sepsis-induced bacterial burden and organ injury, which was blunted by AhR inhibitor. Next, and vitro, IPA enhanced the macrophage phagocytosis through AhR. Depletion of macrophages reversed the protective effects of IPA on sepsis. Finally, on the day of ICU admission (day 0), septic patients had significantly lower IPA level in feces than patient controls. Also, septic patients with bacteremia had significantly lower IPA levels in feces compared with those with non-bacteremia. Furthermore, in septic patients, reduced IPA was associated with worse clinical outcomes, and IPA in feces had similar prediction ability of 28-day mortality with SOFA score, and increased the predictive ability of SOFA score. These findings indicate that gut microbiota-derived IPA can protect against sepsis through host control of infection by promoting macrophages phagocytosis and suggest that IPA may be a new strategy for sepsis treatment.
Topics: Animals; Humans; Mice; Bacteria; Gastrointestinal Microbiome; Indoles; Macrophages; Mice, Inbred C57BL; Phagocytosis; Receptors, Aryl Hydrocarbon; Sepsis
PubMed: 36299625
DOI: 10.3389/fcimb.2022.1015386 -
Trends in Cancer Aug 2023Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However,... (Review)
Review
Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However, innate immune checkpoints, which can hinder the detection and clearance of malignant cells, are also crucial in tumor-mediated immune escape and may also serve as targets in cancer immunotherapy. In this review, we discuss the current understanding of immune evasion by cancer cells via disruption of phagocytic clearance, and the potential effects of blocking phagocytosis checkpoints on the activation of antitumor immune responses. We propose that a more effective combination immunotherapy strategy could be to exploit tumor-intrinsic processes that inhibit key innate immune surveillance processes, such as phagocytosis, and incorporate both innate and adaptive immune responses for treating patients with cancer.
Topics: Humans; Immunity, Innate; Phagocytosis; Neoplasms; Immunotherapy
PubMed: 37150626
DOI: 10.1016/j.trecan.2023.04.006