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Neuron Oct 2018Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific...
Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs.
Topics: Animals; CD47 Antigen; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurogenesis; Neuronal Plasticity; Phagocytosis; Receptors, Immunologic; Synapses
PubMed: 30308165
DOI: 10.1016/j.neuron.2018.09.017 -
Journal For Immunotherapy of Cancer Dec 2020Tumor-associated macrophage (TAM) phagocytic activity is emerging as a new mechanism to harness for cancer treatment. Currently, many approaches are investigated at the... (Review)
Review
Tumor-associated macrophage (TAM) phagocytic activity is emerging as a new mechanism to harness for cancer treatment. Currently, many approaches are investigated at the preclinical level and some modalities have now reached clinical trials, including the targeting of the phagocytosis inhibitor CD47. The rationale for increasing TAM phagocytic activity is to improve innate anticancer immunity, and to promote T-cell mediated adaptive immune responses. In this context, a clear understanding of the impact of TAM phagocytosis on both innate and adaptive immunity is critical. Indeed, uncertainties persist regarding the capacity of TAM to present tumor antigens to CD8 T cells by cross-presentation. This process is critical for an optimal cytotoxic T-cell immune response and can be mediated by dendritic cells but also potentially by macrophages. In addition, the engulfment of cancer cells affects TAM functionality, as apoptotic cell uptake (a process termed efferocytosis) promotes macrophage anti-inflammatory functions. Because of the abundance of TAM in most solid tumors and the common use of apoptosis inducers such as radiotherapy to treat patients with cancer, efferocytosis potentially affects the overall immune balance within the tumor microenvironment (TME). In this review, we will discuss how cancer cell phagocytosis by TAM impacts antitumor immunity. First, we will focus on the potential of the phagocytic activity of TAM per se to control tumor progression. Second, we will examine the potential of TAM to act as antigen presenting cells for tumor specific CD8 T cells, considering the different characteristics of this process in the tumor tissue and at the molecular level. Finally, we will see how phagocytosis and efferocytosis affect TAM functionality and how these mechanisms impact on antitumor immunity. A better understanding of these aspects will enable us to better predict and interpret the consequences of cancer therapies on the immune status of the TME. Future cancer treatment regimens can thereby be designed to not only impact directly on cancer cells, but also to favorably modulate TAM phagocytic activity to benefit from the potential of this central immune player to achieve more potent therapeutic efficacy.
Topics: Disease Progression; Humans; Macrophages; Phagocytosis; Tumor Microenvironment
PubMed: 33335026
DOI: 10.1136/jitc-2020-001408 -
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 -
Journal of Neuroinflammation Mar 2017Ganoderma lucidum (GL) has been widely used in Asian countries for hundreds of years to promote health and longevity. The pharmacological functions of which had been...
BACKGROUND
Ganoderma lucidum (GL) has been widely used in Asian countries for hundreds of years to promote health and longevity. The pharmacological functions of which had been classified, including the activation of innate immune responses, suppression of tumour and modulation of cell proliferations. Effective fractions of Ganoderma lucidum polysaccharides (GLP) had already been reported to regulate the immune system. Nevertheless, the role of GLP in the microglia-mediated neuroinflammation has not been sufficiently elucidated. Further, GLP effect on microglial behavioural modulations in correlation with the inflammatory responses remains to be unravelled. The aim of this work was to quantitatively analyse the contributions of GLP on microglia.
METHODS
The BV2 microglia and primary mouse microglia were stimulated by lipopolysaccharides (LPS) and amyloid beta (Aβ) oligomer, respectively. Investigation on the effect of GLP was carried by quantitative determination of the microglial pro- and anti-inflammatory cytokine expressions and behavioural modulations including migration, morphology and phagocytosis. Analysis of microglial morphology and phagocytosis modulations was confirmed in the zebrafish brain.
RESULTS
Quantitative results revealed that GLP down-regulates LPS- or Aβ-induced pro-inflammatory cytokines and promotes anti-inflammatory cytokine expressions in BV-2 and primary microglia. In addition, GLP attenuates inflammation-related microglial migration, morphological alterations and phagocytosis probabilities. We also showed that modulations of microglial behavioural responses were associated with MCP-1 and C1q expressions.
CONCLUSIONS
Overall, our study provides an insight into the GLP regulation of LPS- and Aβ-induced neuroinflammation and serves an implication that the neuroprotective function of GLP might be achieved through modulation of microglial inflammatory and behavioural responses.
Topics: Animals; Cell Line; Drugs, Chinese Herbal; Inflammation; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Phagocytosis; Polysaccharides; Reishi; Zebrafish
PubMed: 28340576
DOI: 10.1186/s12974-017-0839-0 -
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 -
Progress in Retinal and Eye Research Sep 2017The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and... (Review)
Review
The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.
Topics: Humans; Immunity, Innate; Macular Degeneration; Mitochondria; Oxidative Stress; Phagocytosis; Retinal Pigment Epithelium; Risk Factors
PubMed: 28336424
DOI: 10.1016/j.preteyeres.2017.03.002 -
Immunity May 2019Nearly every tissue in the body undergoes routine turnover of cells as part of normal healthy living. The majority of these cells undergoing turnover die via apoptosis,... (Review)
Review
Nearly every tissue in the body undergoes routine turnover of cells as part of normal healthy living. The majority of these cells undergoing turnover die via apoptosis, and then are rapidly removed by phagocytes by the process of efferocytosis that is anti-inflammatory. However, a number of pathologies have recently been linked to defective clearance of apoptotic cells. Perturbed clearance arises for many reasons, including overwhelming of the clearance machinery, disruptions at different stages of efferocytosis, and responses of phagocytes during efferocytosis, all of which can alter the homeostatic tissue environment. This review covers linkages of molecules involved in the different phases of efferocytosis to disease pathologies that can arise due to their loss or altered function.
Topics: Apoptosis; Erythrocytes; Homeostasis; Humans; Phagocytes; Phagocytosis
PubMed: 31117011
DOI: 10.1016/j.immuni.2019.04.018 -
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