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Developmental and Comparative Immunology Oct 2023Leukocyte immune-type receptors (LITRs) are a large family of teleost immunoregulatory receptor-types belonging to the immunoglobulin superfamily. These immune genes are... (Review)
Review
Leukocyte immune-type receptors (LITRs) are a large family of teleost immunoregulatory receptor-types belonging to the immunoglobulin superfamily. These immune genes are phylogenetically and syntenically related to Fc receptor-like protein genes (fcrls) present in other vertebrates, including amphibians, birds, mice, and man. In vitro-based functional analyses of LITRs, using transfection approaches, have shown that LITRs have diverse immunoregulatory potentials including the activation and inhibition of several innate immune effector responses such as cell-mediated killing responses, degranulation, cytokine secretion, and phagocytosis. The purpose of this mini review is to provide an overview of fish LITR-mediated immunoregulatory potentials obtained from various teleost model systems, including channel catfish, zebrafish, and goldfish. We will also describe preliminary characterization of a new goldish LITR-specific polyclonal antibody (pAb) and discuss the significance of this tool for further investigation of the functions of fish LITRs.
Topics: Mice; Animals; Zebrafish; Receptors, Immunologic; Phagocytosis; Immunity, Innate; Leukocytes
PubMed: 37414235
DOI: 10.1016/j.dci.2023.104768 -
Cell Reports Aug 2020Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a...
Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a major role in inflammation, we studied the contribution of Mfn2 to the activity of these cells. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) induced Mfn2 expression. The use of the Mfn2 and Mfn1 myeloid-conditional knockout (KO) mouse models reveals that Mfn2 but not Mfn1 is required for the adaptation of mitochondrial respiration to stress conditions and for the production of reactive oxygen species (ROS) upon pro-inflammatory activation. Mfn2 deficiency specifically impairs the production of pro-inflammatory cytokines and nitric oxide. In addition, the lack of Mfn2 but not Mfn1 is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. Mfn2 mice fail to be protected from Listeria, Mycobacterium tuberculosis, or LPS endotoxemia. These results reveal an unexpected contribution of Mfn2 to ROS production and inflammation in macrophages.
Topics: Animals; Autophagy; GTP Phosphohydrolases; Mice; Mitochondria; Phagocytosis; Reactive Oxygen Species
PubMed: 32846136
DOI: 10.1016/j.celrep.2020.108079 -
Blood Jun 2022Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing...
Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing through cellular phagocytosis have emerged as promising cancer immunotherapy. Although several phagocytosis checkpoints have been identified, the desired efficacy has not yet been achieved by blocking such checkpoints in preclinical models or clinical trials. Here, we showed that late-stage non-Hodgkin lymphoma (NHL) was resistant to therapy targeting phagocytosis checkpoint CD47 due to the compromised capacity of TAMs to phagocytose lymphoma cells. Via a high-throughput screening of the US Food and Drug Administration-approved anticancer small molecule compounds, we identified paclitaxel as a potentiator that promoted the clearance of lymphoma by directly evoking phagocytic capability of macrophages, independently of paclitaxel's chemotherapeutic cytotoxicity toward NHL cells. A combination with paclitaxel dramatically enhanced the anticancer efficacy of CD47-targeted therapy toward late-stage NHL. Analysis of TME by single-cell RNA sequencing identified paclitaxel-induced TAM populations with an upregulation of genes for tyrosine kinase signaling. The activation of Src family tyrosine kinases signaling in macrophages by paclitaxel promoted phagocytosis against NHL cells. In addition, we identified a role of paclitaxel in modifying the TME by preventing the accumulation of a TAM subpopulation that was only present in late-stage lymphoma resistant to CD47-targeted therapy. Our findings identify a novel and effective strategy for NHL treatment by remodeling TME to enable the tumoricidal roles of TAMs. Furthermore, we characterize TAM subgroups that determine the efficiency of lymphoma phagocytosis in the TME and can be potential therapeutic targets to unleash the antitumor activities of macrophages.
Topics: CD47 Antigen; Humans; Immunosuppression Therapy; Immunotherapy; Lymphoma; Macrophages; Neoplasms; Paclitaxel; Phagocytosis; Tumor Microenvironment
PubMed: 35134139
DOI: 10.1182/blood.2021013901 -
Biochemical Society Transactions Oct 2022Phagocytosis triggered by the phospholipid phosphatidylserine (PS) is key for the removal of apoptotic cells in development, tissue homeostasis and infection. Modulation... (Review)
Review
Phagocytosis triggered by the phospholipid phosphatidylserine (PS) is key for the removal of apoptotic cells in development, tissue homeostasis and infection. Modulation of PS-mediated phagocytosis is an attractive target for therapeutic intervention in the context of atherosclerosis, neurodegenerative disease, and cancer. Whereas the mechanisms of target recognition, lipid and protein signalling, and cytoskeletal remodelling in opsonin-driven modes of phagocytosis are increasingly well understood, PS-mediated phagocytosis has remained more elusive. This is partially due to the involvement of a multitude of receptors with at least some redundancy in functioning, which complicates dissecting their contributions and results in complex downstream signalling networks. This review focusses on the receptors involved in PS-recognition, the signalling cascades that connect receptors to cytoskeletal remodelling required for phagocytosis, and recent progress in our understanding of how phagocytic cup formation is coordinated during PS-mediated phagocytosis.
Topics: Humans; Phosphatidylserines; Neurodegenerative Diseases; Apoptosis; Phagocytosis; Signal Transduction
PubMed: 36281986
DOI: 10.1042/BST20211254 -
International Journal of Molecular... Oct 2023Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells... (Review)
Review
Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is called efferocytosis. If the process fails, this may cause different types of diseases. More and more evidence suggests that a faulty efferocytosis process is closely related to the pathological processes of respiratory diseases. In this review, we will first introduce the process and the related mechanisms of efferocytosis of the macrophage. Secondly, we will propose some methods that can regulate the function of efferocytosis at different stages of the process. Next, we will discuss the role of efferocytosis in different lung diseases and the related treatment approaches. Finally, we will summarize the drugs that have been applied in clinical practice that can act upon efferocytosis, in order to provide new ideas for the treatment of lung diseases.
Topics: Humans; Apoptosis; Phagocytosis; Macrophages; Phagocytes; Lung Diseases; Respiration Disorders
PubMed: 37834319
DOI: 10.3390/ijms241914871 -
Biochemical Society Transactions Jun 2023Phagocytosis is an evolutionarily conserved important immunological process in higher organisms, and acts as the first line of defense against invading pathogenic... (Review)
Review
Phagocytosis is an evolutionarily conserved important immunological process in higher organisms, and acts as the first line of defense against invading pathogenic microbial infections. Additionally, this dynamic innate immune response is also critical for clearing apoptotic cells and/or tissues, is responsible for maintaining homeostasis and acts as a systemic regulator of critical physiological processes such as wound healing and tissue regeneration. Over the past two decades, numerous studies have shown that phagocytosis occurs in three spatiotemporally distinct steps, namely formation, maturation and resolution of the phagosome, and that, both the protein and lipid composition change as a function of the aforementioned steps during this immunological process. While significant knowledge is now available on the proteomic content of a phagosome during the different stages of phagocytosis, the lipidome however, remained lesser explored, until the past few years. In this review, we summarize recent efforts towards mapping the physiological roles and functions of three lipid classes, the phosphatidylinositols, cholesterol and sphingolipids during the various stages of phagocytosis, and discuss strategies evolved by microbes to hijack and/or disrupt these lipid pathways to evade the immune system. We conclude this review with some potential avenues that may be pursued towards mapping hitherto unknown lipid pathways during phagocytosis, and how this research might be beneficial in our ongoing battle to overcome pathogenic infections.
Topics: Proteomics; Phagocytosis; Phagosomes; Phosphatidylinositols; Immunity, Innate
PubMed: 37314030
DOI: 10.1042/BST20221424 -
Blood Nov 2022
Topics: Leukocytes; Phagocytosis
PubMed: 36394903
DOI: 10.1182/blood.2022017826 -
Cells Oct 2022Microglia, the main immune modulators of the central nervous system, have key roles in both the developing and adult brain. These functions include shaping healthy... (Review)
Review
Microglia, the main immune modulators of the central nervous system, have key roles in both the developing and adult brain. These functions include shaping healthy neuronal networks, carrying out immune surveillance, mediating inflammatory responses, and disposing of unwanted material. A wide variety of pathological conditions present with microglia dysregulation, highlighting the importance of these cells in both normal brain function and disease. Studies into microglial function in the context of both health and disease thus have the potential to provide tremendous insight across a broad range of research areas. In vitro culture of microglia, using primary cells, cell lines, or induced pluripotent stem cell derived microglia, allows researchers to generate reproducible, robust, and quantifiable data regarding microglia function. A broad range of assays have been successfully developed and optimised for characterizing microglial morphology, mediation of inflammation, endocytosis, phagocytosis, chemotaxis and random motility, and mediation of immunometabolism. This review describes the main functions of microglia, compares existing protocols for measuring these functions in vitro, and highlights common pitfalls and future areas for development. We aim to provide a comprehensive methodological guide for researchers planning to characterise microglial functions within a range of contexts and in vitro models.
Topics: Microglia; Phagocytosis; Chemotaxis; Central Nervous System; Brain
PubMed: 36359810
DOI: 10.3390/cells11213414 -
Current Biology : CB Jan 2021New work shows that the glycocalyx meshwork on the surface of macrophages prevents phagocytic receptors from binding their ligands by two means - electrostatic charge...
New work shows that the glycocalyx meshwork on the surface of macrophages prevents phagocytic receptors from binding their ligands by two means - electrostatic charge and steric hindrance. Components of this barrier are present on pathogenic and malignant targets that elude phagocytosis.
Topics: Glycocalyx; Ligands; Macrophages; Phagocytes; Phagocytosis
PubMed: 33434480
DOI: 10.1016/j.cub.2020.10.066 -
ELife Dec 2022The centrosome decides which branch extending from the body of microglia will successfully engulf and clear away dead neurons.
The centrosome decides which branch extending from the body of microglia will successfully engulf and clear away dead neurons.
Topics: Centrosome; Microglia; Neurons; Phagocytosis
PubMed: 36508246
DOI: 10.7554/eLife.84659