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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 -
Immunity May 2012The chemokine superfamily consists of a large number of ligands and receptors. At first glance, this family appears redundant and their ligand-receptor relationships... (Review)
Review
The chemokine superfamily consists of a large number of ligands and receptors. At first glance, this family appears redundant and their ligand-receptor relationships promiscuous, making its study challenging. However, analyzing this family from the evolutionary perspective greatly simplifies understanding both the organization and function of this apparently complex system. In particular, the functions of a subgroup of chemokines (designated homeostatic chemokines) have played pivotal roles in advancing our understanding of the organization and function of the cellular networks that shape the immune system. Here, we update the full scope of the human and mouse chemokine superfamilies and their relationships and summarize several important roles that homeostatic chemokines play in the immune system.
Topics: Animals; Chemokines; Humans; Immune System; Ligands; Receptors, Chemokine
PubMed: 22633458
DOI: 10.1016/j.immuni.2012.05.008 -
Cold Spring Harbor Perspectives in... Jan 2015Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system.... (Review)
Review
Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. They also recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses.
Topics: Chemokines; Homeostasis; Humans; Immunity, Innate; Inflammation
PubMed: 25635046
DOI: 10.1101/cshperspect.a016303 -
Cancer Communications (London, England) May 2023Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and... (Review)
Review
Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.
Topics: Humans; Tumor Microenvironment; Neoplasms; Signal Transduction; Neoplastic Processes; Receptors, Chemokine; Chemokines
PubMed: 37005490
DOI: 10.1002/cac2.12416 -
Advances in Clinical and Experimental... Jun 2018The aim of this review is to present data from the available literature concerning CXCL9, CXCL10 and CXCL11, as well as their receptor 3 (CXCR3) in selected diseases of... (Review)
Review
The aim of this review is to present data from the available literature concerning CXCL9, CXCL10 and CXCL11, as well as their receptor 3 (CXCR3) in selected diseases of the central nervous system (CNS), such as tickborne encephalitis (TBE), neuroborreliosis (NB), Alzheimer's disease (AD), and multiple sclerosis (MS). CXCL9, CXCL10, and CXCL11 lack glutamic acid-leucine-arginine (ELR), and are unique, because they are more closely related to each other than to any other chemokine. The aforementioned chemokines are especially involved in Th1-type response and in various diseases, as their expression correlates with the tissue infiltration of T cells. Their production is strongly induced by interferon gamma (IFN-υ), the most typical Th1 cytokine. They act by binding to the CXC3 receptor. Knowledge about the action mechanism of CXCR3 and its ligands may be useful in the treatment of CNS diseases. However, data in the literature concerning the evaluation of CXCL9, CXCL10, CXCL11, and their receptor with the use of the enzyme-linked immunosorbent assay (ELISA) method is limited.
Topics: Central Nervous System Diseases; Chemokine CXCL10; Chemokine CXCL11; Chemokine CXCL9; Chemokines; Humans; Nerve Degeneration; Neurodegenerative Diseases; Receptors, CXCR3
PubMed: 29893515
DOI: 10.17219/acem/68846 -
Biomedical Journal Jun 2022In this issue of Biomedical Journal we encounter the chemokine superfamily and its clinical potential. The time course from 56 days zero COVID-19 to a resurgence in...
In this issue of Biomedical Journal we encounter the chemokine superfamily and its clinical potential. The time course from 56 days zero COVID-19 to a resurgence in cases is presented, as well as a possible solution to overcome rejection in vascularized composite allotransplantation. We are shown the opportunity deep learning (DL) offers in the case of tracking single cells and particles, and also use of DL to bring all hands on deck to counter the current challenge of the COVID-19 pandemic. This issue contains articles about the effect of low energy shock waves in cystitis; the negative effect of high fructose on aortic valve stenosis; a study about the outcome of fecal microbiota transplantation in case of refractory Clostridioides difficile infection; a novel long non-coding RNA that could serve in treating triple-negative breast cancer; the benefits of acupressure in patients with restless leg syndrome; and Filamin A mutations in abnormal neuronal migration development. Finally, a link between jaw surgery and the psychological impact on the patient is explored; a method presented that allows identification of cervical characteristics associated with difficult embryo transfer; and a letter suggesting new parameters to evaluate the use of bone-substitute augmentation in the treatment of osteoporotic intertrochanteric fractures.
Topics: COVID-19; Chemokines; Clostridium Infections; Fecal Microbiota Transplantation; Humans; Treatment Outcome
PubMed: 35697204
DOI: 10.1016/j.bj.2022.06.001 -
Frontiers in Immunology 2023CCL13/MCP-4 belongs to the CC chemokine family, which induces chemotaxis in many immune cells. Despite extensive research into its function in numerous disorders, a... (Review)
Review
CCL13/MCP-4 belongs to the CC chemokine family, which induces chemotaxis in many immune cells. Despite extensive research into its function in numerous disorders, a thorough analysis of CCL13 is not yet accessible. The role of CCL13 in human disorders and existing CCL13-focused therapies are outlined in this study. The function of CCL13 in rheumatic diseases, skin conditions, and cancer is comparatively well-established, and some studies also suggest that it may be involved in ocular disorders, orthopedic conditions, nasal polyps, and obesity. We also give an overview of research that found very little evidence of CCL13 in HIV, nephritis, and multiple sclerosis. Even though CCL13-mediated inflammation is frequently linked to disease pathogenesis, it's fascinating to note that in some conditions, like primary biliary cholangitis (PBC) and suicide, it might even act as a preventative measure.
Topics: Humans; Chemokines, CC; Monocyte Chemoattractant Proteins
PubMed: 37153575
DOI: 10.3389/fimmu.2023.1176639 -
Journal of Interferon & Cytokine... Feb 2017Several chemokines have important functions in mucosal immunity. While there are many chemokines, 4 of them (CCL25, CCL28, CXCL14, and CXCL17) are especially important... (Review)
Review
Several chemokines have important functions in mucosal immunity. While there are many chemokines, 4 of them (CCL25, CCL28, CXCL14, and CXCL17) are especially important in mucosal immunity because they are homeostatically expressed in mucosal tissues. Of these, only CCL25 and CCL28 have been widely recognized as mucosal chemokines. In this study, we review the physiology of these chemokines with specific emphasis on their function in mucosal immunity. CCL25 recruits certain important subsets of T cells that express CCR9 to the small intestine. These CCR9 T cells also express the integrin α4β7 and have been shown to play important roles in the control of intestinal inflammation. CCL28 recruits CCR10 IgA plasmablasts to the lactating mammary gland. The role of CXCL14 in mucosal immunity is less well defined, but a Cxcl14 mouse exhibits significant metabolic abnormalities. Finally, CXCL17 was the last chemokine to be described and signals through a new chemokine receptor (GPR35/CXCR8), which is expressed in a subset of macrophages that are recruited to mucosal tissues by this chemokine. We conclude that these 4 chemokines play very important roles in mucosal immunity and their continued functional characterization will likely identify novel therapeutic targets.
Topics: Adaptive Immunity; Animals; Biomarkers; Chemokines; Disease Susceptibility; Gene Expression Regulation; Humans; Immunity, Innate; Immunity, Mucosal; Mucous Membrane; Signal Transduction
PubMed: 28207301
DOI: 10.1089/jir.2016.0076 -
Einstein (Sao Paulo, Brazil) 2015Chemokines are a large family of small cytokines and generally have low molecular weight ranging from 7 to 15kDa. Chemokines and their receptors are able to control the... (Review)
Review
Chemokines are a large family of small cytokines and generally have low molecular weight ranging from 7 to 15kDa. Chemokines and their receptors are able to control the migration and residence of all immune cells. Some chemokines are considered pro-inflammatory, and their release can be induced during an immune response at a site of infection, while others are considered homeostatic and are involved in controlling of cells migration during tissue development or maintenance. The physiologic importance of this family of mediators is resulting from their specificity - members of the chemokine family induce recruitment of well-defined leukocyte subsets. There are two major chemokine sub-families based upon cysteine residues position: CXC and CC. As a general rule, members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and sub-set of lymphocytes, although there are some exceptions. This review discusses the potential role of chemokines in inflammation focusing on the two best-characterized chemokines: monocyte chemoattractant protein-1, a CC chemokine, and interleukin-8, a member of the CXC chemokine sub-family.
Topics: Acute Disease; Chemokine CCL2; Chemokines; Humans; Inflammation; Interleukin-8; Peptide Fragments
PubMed: 26466066
DOI: 10.1590/S1679-45082015RB3438 -
Annual Review of Biophysics May 2017Chemokines and their cell surface G protein-coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory... (Review)
Review
Chemokines and their cell surface G protein-coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.
Topics: Allosteric Regulation; Animals; Chemokines; Crystallography, X-Ray; Drug Discovery; Humans; Models, Molecular; Receptors, Chemokine
PubMed: 28532213
DOI: 10.1146/annurev-biophys-051013-022942