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The FEBS Journal Aug 2018The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein-coupled heptahelical chemokine... (Review)
Review
The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein-coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behavior, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many nonleukocytic cell types. Chemokines are profoundly affected by post-translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical 'atypical' chemokine receptors that regulate chemokine localization and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarizes the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focusing particularly on their ability to direct leukocyte migration.
Topics: Animals; Cell Movement; Chemokines; Chemotaxis; Glycosaminoglycans; Homeostasis; Host-Pathogen Interactions; Humans; Infections; Inflammation; Protein Multimerization; Protein Processing, Post-Translational; Receptors, Chemokine
PubMed: 29637711
DOI: 10.1111/febs.14466 -
Frontiers in Immunology 2019Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to... (Review)
Review
Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to harness immune cells: monoclonal antibodies against tumor antigens, immune checkpoint inhibitors, vaccination, adoptive cell therapies (e.g., CAR-T cells) and cytokine administration. In the last decades, it is emerging that the chemokine system represents a potential target for immunotherapy. Chemokines, a large family of cytokines with chemotactic activity, and their cognate receptors are expressed by both cancer and stromal cells. Their altered expression in malignancies dictates leukocyte recruitment and activation, angiogenesis, cancer cell proliferation, and metastasis in all the stages of the disease. Here, we review first attempts to inhibit the chemokine system in cancer as a monotherapy or in combination with canonical or immuno-mediated therapies. We also provide recent findings about the role in cancer of atypical chemokine receptors that could become future targets for immunotherapy.
Topics: Antibodies, Monoclonal, Humanized; Benzylamines; Chemokines, CC; Chemokines, CXC; Cyclams; Heterocyclic Compounds; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Receptors, CCR; Receptors, CXCR
PubMed: 30894861
DOI: 10.3389/fimmu.2019.00379 -
Immunity May 2020Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced...
Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8 T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.
Topics: Animals; Cell Line, Tumor; Cytotoxicity, Immunologic; Extracellular Traps; HT29 Cells; Humans; Intravital Microscopy; Killer Cells, Natural; Ligands; Mice; Neoplasms, Experimental; Receptors, Chemokine; Receptors, Interleukin-8A; Receptors, Interleukin-8B; T-Lymphocytes, Cytotoxic
PubMed: 32289253
DOI: 10.1016/j.immuni.2020.03.001 -
International Journal of Molecular... Nov 2017Inflammation is the body's response to injury or infection. As early as 2000 years ago, the Roman encyclopaedist Aulus Cornelius Celsus recognised four cardinal signs of...
Inflammation is the body's response to injury or infection. As early as 2000 years ago, the Roman encyclopaedist Aulus Cornelius Celsus recognised four cardinal signs of this response-redness, heat, swelling and pain; a fifth sign is loss of function.[...].
Topics: Biophysical Phenomena; Chemokines; Glycosaminoglycans; Humans; Inflammation; Protein Multimerization; Receptors, Chemokine
PubMed: 29135930
DOI: 10.3390/ijms18112415 -
Cell Dec 2013Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia...
Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.
Topics: Animals; Brain-Derived Neurotrophic Factor; CX3C Chemokine Receptor 1; Gene Expression; Learning; Mice; Microglia; Neuronal Plasticity; Protein Kinases; Receptors, Chemokine; Signal Transduction; Synapses
PubMed: 24360280
DOI: 10.1016/j.cell.2013.11.030 -
Immunity Aug 2023T cells differentiate into functionally distinct states upon antigen encounter. These states are delineated by different cell surface markers for murine and human...
T cells differentiate into functionally distinct states upon antigen encounter. These states are delineated by different cell surface markers for murine and human T cells, which hamper cross-species translation of T cell properties. We aimed to identify surface markers that reflect the graded nature of CD8 T cell differentiation and delineate functionally comparable states in mice and humans. CITEseq analyses revealed that graded expression of CX3CR1, encoding the chemokine receptor CX3CR1, correlated with the CD8 T cell differentiation gradient. CX3CR1 expression distinguished human and murine CD8 and CD4 T cell states, as defined by migratory and functional properties. Graded CX3CR1 expression, refined with CD62L, accurately captured the high-dimensional T cell differentiation continuum. Furthermore, the CX3CR1 expression gradient delineated states with comparable properties in humans and mice in steady state and on longitudinally tracked virus-specific CD8 T cells in both species. Thus, graded CX3CR1 expression provides a strategy to translate the behavior of distinct T cell differentiation states across species.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cell Differentiation; CX3C Chemokine Receptor 1; Immunologic Memory; Receptors, Chemokine
PubMed: 37490909
DOI: 10.1016/j.immuni.2023.06.025 -
Nature Immunology Oct 2014The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the...
The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.
Topics: Animals; Animals, Newborn; Antigens, Differentiation; Antigens, Ly; Bone Marrow Transplantation; CD11b Antigen; CX3C Chemokine Receptor 1; Cell Differentiation; Cell Proliferation; Flow Cytometry; Gene Expression; Intestinal Mucosa; Intestines; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Immunological; Monocytes; Parabiosis; Receptors, CCR2; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; Time Factors
PubMed: 25151491
DOI: 10.1038/ni.2967 -
Progress in Molecular Biology and... 2013Oligomerization of chemokine receptors has been reported to influence many aspects of receptor function through allosteric communication between receptor protomers.... (Review)
Review
Oligomerization of chemokine receptors has been reported to influence many aspects of receptor function through allosteric communication between receptor protomers. Allosteric interactions within chemokine receptor hetero-oligomers have been shown to cause negative cooperativity in the binding of chemokines and to inhibit receptor activation in the case of some receptor pairs. Other receptor pairs can cause enhanced signaling and even activate entirely new, hetero-oligomer-specific signaling complexes and responses downstream of receptor activation. Many mechanisms contribute to these effects including direct allosteric coupling between the receptors, G protein-mediated allostery, G protein stealing, ligand sequestration, and recruitment of new intracellular proteins by exposing unique binding interfaces on the oligomerized receptors. These effects present both challenges as well as exciting opportunities for drug discovery. One of the most difficult challenges will involve determining if and when hetero-oligomers versus homomeric receptors are involved in specific disease states.
Topics: Allosteric Regulation; Animals; Humans; Ligands; Models, Molecular; Protein Binding; Protein Multimerization; Receptors, Chemokine
PubMed: 23415099
DOI: 10.1016/B978-0-12-394587-7.00009-9 -
Journal of Medicinal Chemistry Jun 2017This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor... (Review)
Review
This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure-activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor-ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.
Topics: Binding Sites; Computer Simulation; Crystallography, X-Ray; Humans; Ligands; Models, Molecular; Mutagenesis, Site-Directed; Protein Conformation; Receptors, CCR2; Receptors, CCR5; Receptors, CXCR4; Receptors, Chemokine; Structure-Activity Relationship
PubMed: 28165741
DOI: 10.1021/acs.jmedchem.6b01309 -
Journal of Innate Immunity 2018Viruses use diverse molecular mechanisms to exploit and evade the immune response. Herpesviruses, in particular, encode functional chemokine and chemokine receptor... (Review)
Review
Viruses use diverse molecular mechanisms to exploit and evade the immune response. Herpesviruses, in particular, encode functional chemokine and chemokine receptor homologs pirated from the host, as well as secreted chemokine-binding proteins with unique structures. Multiple functions have been described for herpesvirus chemokine components, including attraction of target cells, blockade of leukocyte migration, and modulation of gene expression and cell entry by the virus. Here we review current concepts about how human herpesvirus chemokines, chemokine receptors, and chemokine-binding proteins may be used to shape a proviral state in the host.
Topics: Animals; Cell Movement; Chemokines; Herpesviridae; Herpesviridae Infections; Host-Pathogen Interactions; Humans; Immune Evasion; Leukocytes; Receptors, Chemokine
PubMed: 30165356
DOI: 10.1159/000492161