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Richard Horuk - One of the best experts on this subject based on the ideXlab platform.
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Chemokine Receptors version 2020 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2020Co-Authors: Francoise Bachelerie, Gerard J. Graham, Adit Benbaruch, Amanda M Burkhardt, Christophe Combadiere, Joshua M Farber, Israel F Charo, Reinhold Forster, Rebecca Hills, Richard HorukAbstract:Chemokine Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [431, 430, 32]) comprise a large subfamily of 7TM proteins that bind one or more Chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many Chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine Receptors can be divided by function into two main groups: G protein-coupled Chemokine Receptors, which mediate leukocyte trafficking, and "Atypical Chemokine Receptors", which may signal through non-G protein-coupled mechanisms and act as Chemokine scavengers to downregulate inflammation or shape Chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-Chemokines; n= 28), CXC (also known as α-Chemokines; n= 17) and CX3C (n= 1) Chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C Chemokines (n= 2) have only the second and fourth cysteines found in other Chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most Chemokine Receptors are able to bind multiple high-affinity Chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most Chemokines bind to more than one receptor subtype. Receptors for inflammatory Chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled Chemokine Receptors are named acccording to the class of Chemokines bound, whereas ACKR is the root acronym for atypical Chemokine Receptors [33]. There can be substantial cross-species differences in the sequences of both Chemokines and Chemokine Receptors, and in the pharmacology and biology of Chemokine Receptors. Endogenous and microbial non-Chemokine ligands have also been identified for Chemokine Receptors. Many Chemokine Receptors function as HIV co-Receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard Chemokine receptor names [684] and aliases.
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Chemokine Receptors version 2019 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Francoise Bachelerie, Gerard J. Graham, Adit Benbaruch, Richard Horuk, Christophe Combadiere, Joshua M Farber, Israel F Charo, Reinhold Forster, Rebecca Hills, Massimo LocatiAbstract:Chemokine Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [426, 425, 32]) comprise a large subfamily of 7TM proteins that bind one or more Chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many Chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine Receptors can be divided by function into two main groups: G protein-coupled Chemokine Receptors, which mediate leukocyte trafficking, and "Atypical Chemokine Receptors", which may signal through non-G protein-coupled mechanisms and act as Chemokine scavengers to downregulate inflammation or shape Chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-Chemokines; n= 28), CXC (also known as α-Chemokines; n= 17) and CX3C (n= 1) Chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C Chemokines (n= 2) have only the second and fourth cysteines found in other Chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most Chemokine Receptors are able to bind multiple high-affinity Chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most Chemokines bind to more than one receptor subtype. Receptors for inflammatory Chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled Chemokine Receptors are named acccording to the class of Chemokines bound, whereas ACKR is the root acronym for atypical Chemokine Receptors [33]. There can be substantial cross-species differences in the sequences of both Chemokines and Chemokine Receptors, and in the pharmacology and biology of Chemokine Receptors. Endogenous and microbial non-Chemokine ligands have also been identified for Chemokine Receptors. Many Chemokine Receptors function as HIV co-Receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard Chemokine receptor names [675] and aliases.
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recent progress in the development of antagonists to the Chemokine Receptors ccr3 and ccr4
Expert Opinion on Drug Discovery, 2014Co-Authors: James E Pease, Richard HorukAbstract:Introduction: The Chemokine Receptors CCR3 and CCR4 have been shown to be important therapeutic targets for the treatment of a variety of diseases. Although only two Chemokine receptor inhibitors have been approved so far, there are numerous compounds that are in various stages of development. Areas covered: In this review article, the authors provide an update on the progress made in the identification of antagonists against the Chemokine Receptors CCR3 and CCR4 from 2009 to the present. The rationale of writing this review article is to cover the most important approaches to identifying antagonists to these two Receptors, which could prove to be useful therapeutics in treating proinflammatory diseases. Expert opinion: Pharmaceutical companies have expended a considerable amount of money and effort to identify potent inhibitors of CCR3 and CCR4 for the treatment of asthma and atopic diseases. Although a variety of compounds have been described and several have progressed into the clinic, none have so far...
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international union of pharmacology lxxxix update on the extended family of Chemokine Receptors and introducing a new nomenclature for atypical Chemokine Receptors
Pharmacological Reviews, 2014Co-Authors: Francoise Bachelerie, Massimo Locati, Gerard J. Graham, Adit Benbaruch, Richard Horuk, Amanda M Burkhardt, Christophe Combadiere, Joshua M Farber, Alexander Hovard Sparreulrich, Andrew D LusterAbstract:Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled Chemokine Receptors, the large family of leukocyte chemoattractant Receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since then, several new Receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at Chemokine Receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical Chemokine Receptors has emerged that may signal through arrestins instead of G proteins to act as Chemokine scavengers, and many microbial and invertebrate G protein-coupled Chemokine Receptors and soluble Chemokine-binding proteins have been described. Here, we review this extended family of Chemokine Receptors and Chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical Chemokine Receptors with the stem ACKR (atypical Chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.
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Chemokines, Chemokine Receptors and small-molecule antagonists: recent developments.
Trends in pharmacological sciences, 2002Co-Authors: James Onuffer, Richard HorukAbstract:The physiological roles of Chemokine Receptors have expanded beyond host defense and now represent important targets for intervention in several disease indications. Chemokine Receptors have joined the ranks of other members of the G-protein-coupled receptor (GPCR) family in therapeutic potential as small-molecule Chemokine receptor antagonists move from discovery to the clinic. Chemokine Receptors belong to the rhodopsin family of GPCRs and, as such, are expected to be closely related in structure to other Class A members. In this review, we summarize information that is pertinent to Chemokine Receptors as therapeutic targets, the status of low molecular weight antagonists in clinical development, molecular modeling of receptor-small-molecule interactions, and the challenges that face drug discovery and development programs.
E Leslie M D Silberstein - One of the best experts on this subject based on the ideXlab platform.
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human bone marrow stromal cells express a distinct set of biologically functional Chemokine Receptors
Stem Cells, 2006Co-Authors: Marek Honczarenko, Yi Le, Marcin Swierkowski, Aleksandra M Glodek, Ionita Ghiran, E Leslie M D SilbersteinAbstract:Stromal cells isolated from bone marrow (BMSCs), often referred to as mesenchymal stem cells, are currently under investigation for a variety of therapeutic applications. However, limited data are available regarding Receptors that can influence their homing to and positioning within the bone marrow. In the present study, we found that second passage BMSCs express a unique set of Chemokine Receptors: three CC Chemokine Receptors (CCR1, CCR7, and CCR9) and three CXC Chemokine Receptors (CXCR4, CXCR5, and CXCR6). BMSCs cultured in serum-free medium secrete several Chemokine ligands (CCL2, CCL4, CCL5, CCL20, CXCL12, CXCL8, and CX3CL1). The surface-expressed Chemokine Receptors were functional by several criteria. Stimulation of BMSCs with Chemokine ligands triggers phosphorylation of the mitogen-activated protein kinase (e.g., extracellular signal–related kinase [ERK]-1 and ERK-2) and focal adhesion kinase signaling pathways. In addition, CXCL12 selectively activates signal transducer and activator of transcription (STAT)-5 whereas CCL5 activates STAT-1. In cell biologic assays, all of the Chemokines tested stimulate chemotaxis of BMSCs, and CXCL12 induces cytoskeleton F-actin polymerization. Studies of culture-expanded BMSCs, for example, 12–16 passages, indicate loss of surface expression of all Chemokine Receptors and lack of chemotactic response to Chemokines. The loss in Chemokine receptor expression is accompanied by a decrease in expression of adhesion molecules (ICAM-1, ICAM-2, and vascular cell adhesion molecule 1) and CD157, while expression of CD90 and CD105 is maintained. The change in BMSC phenotype is associated with slowing of cell growth and increased spontaneous apoptosis. These findings suggest that several Chemokine axes may operate in BMSC biology and may be important parameters in the validation of cultured BMSCs intended for cell therapy.
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human bone marrow stromal cells express a distinct set of biologically functional Chemokine Receptors
Stem Cells, 2006Co-Authors: Marek Honczarenko, Yi Le, Marcin Swierkowski, Aleksandra M Glodek, Ionita Ghiran, E Leslie M D SilbersteinAbstract:Stromal cells isolated from bone marrow (BMSCs), often referred to as mesenchymal stem cells, are currently under investigation for a variety of therapeutic applications. However, limited data are available regarding Receptors that can influence their homing to and positioning within the bone marrow. In the present study, we found that second passage BMSCs express a unique set of Chemokine Receptors: three CC Chemokine Receptors (CCR1, CCR7, and CCR9) and three CXC Chemokine Receptors (CXCR4, CXCR5, and CXCR6). BMSCs cultured in serum-free medium secrete several Chemokine ligands (CCL2, CCL4, CCL5, CCL20, CXCL12, CXCL8, and CX3CL1). The surface-expressed Chemokine Receptors were functional by several criteria. Stimulation of BMSCs with Chemokine ligands triggers phosphorylation of the mitogen-activated protein kinase (e.g., extracellular signal–related kinase [ERK]-1 and ERK-2) and focal adhesion kinase signaling pathways. In addition, CXCL12 selectively activates signal transducer and activator of transcription (STAT)-5 whereas CCL5 activates STAT-1. In cell biologic assays, all of the Chemokines tested stimulate chemotaxis of BMSCs, and CXCL12 induces cytoskeleton F-actin polymerization. Studies of culture-expanded BMSCs, for example, 12–16 passages, indicate loss of surface expression of all Chemokine Receptors and lack of chemotactic response to Chemokines. The loss in Chemokine receptor expression is accompanied by a decrease in expression of adhesion molecules (ICAM-1, ICAM-2, and vascular cell adhesion molecule 1) and CD157, while expression of CD90 and CD105 is maintained. The change in BMSC phenotype is associated with slowing of cell growth and increased spontaneous apoptosis. These findings suggest that several Chemokine axes may operate in BMSC biology and may be important parameters in the validation of cultured BMSCs intended for cell therapy.
Gerard J. Graham - One of the best experts on this subject based on the ideXlab platform.
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Chemokine Receptors version 2020 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2020Co-Authors: Francoise Bachelerie, Gerard J. Graham, Adit Benbaruch, Amanda M Burkhardt, Christophe Combadiere, Joshua M Farber, Israel F Charo, Reinhold Forster, Rebecca Hills, Richard HorukAbstract:Chemokine Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [431, 430, 32]) comprise a large subfamily of 7TM proteins that bind one or more Chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many Chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine Receptors can be divided by function into two main groups: G protein-coupled Chemokine Receptors, which mediate leukocyte trafficking, and "Atypical Chemokine Receptors", which may signal through non-G protein-coupled mechanisms and act as Chemokine scavengers to downregulate inflammation or shape Chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-Chemokines; n= 28), CXC (also known as α-Chemokines; n= 17) and CX3C (n= 1) Chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C Chemokines (n= 2) have only the second and fourth cysteines found in other Chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most Chemokine Receptors are able to bind multiple high-affinity Chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most Chemokines bind to more than one receptor subtype. Receptors for inflammatory Chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled Chemokine Receptors are named acccording to the class of Chemokines bound, whereas ACKR is the root acronym for atypical Chemokine Receptors [33]. There can be substantial cross-species differences in the sequences of both Chemokines and Chemokine Receptors, and in the pharmacology and biology of Chemokine Receptors. Endogenous and microbial non-Chemokine ligands have also been identified for Chemokine Receptors. Many Chemokine Receptors function as HIV co-Receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard Chemokine receptor names [684] and aliases.
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Chemokine Receptors coordinately regulate macrophage dynamics and mammary gland development
Development, 2020Co-Authors: Gillian J. Wilson, Ayumi Fukuoka, Samantha Love, Marieke Pingen, Alan J. Hayes, Jiwon Kim, Gerard J. GrahamAbstract:Macrophages are key regulators of developmental processes, including those involved in mammary gland development. We have previously demonstrated that the atypical Chemokine receptor ACKR2 contributes to the control of ductal epithelial branching in the developing mammary gland by regulating macrophage dynamics. ACKR2 is a Chemokine-scavenging receptor that mediates its effects through collaboration with inflammatory Chemokine Receptors (iCCRs). Here, we reveal reciprocal regulation of branching morphogenesis in the mammary gland, whereby stromal ACKR2 modulates levels of the shared ligand CCL7 to control the movement of a key population of CCR1-expressing macrophages to the ductal epithelium. In addition, oestrogen, which is essential for ductal elongation during puberty, upregulates CCR1 expression on macrophages. The age at which girls develop breasts is decreasing, which raises the risk of diseases including breast cancer. This study presents a previously unknown mechanism controlling the rate of mammary gland development during puberty and highlights potential therapeutic targets.
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Chemokine Receptors version 2019 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Francoise Bachelerie, Gerard J. Graham, Adit Benbaruch, Richard Horuk, Christophe Combadiere, Joshua M Farber, Israel F Charo, Reinhold Forster, Rebecca Hills, Massimo LocatiAbstract:Chemokine Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [426, 425, 32]) comprise a large subfamily of 7TM proteins that bind one or more Chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many Chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine Receptors can be divided by function into two main groups: G protein-coupled Chemokine Receptors, which mediate leukocyte trafficking, and "Atypical Chemokine Receptors", which may signal through non-G protein-coupled mechanisms and act as Chemokine scavengers to downregulate inflammation or shape Chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-Chemokines; n= 28), CXC (also known as α-Chemokines; n= 17) and CX3C (n= 1) Chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C Chemokines (n= 2) have only the second and fourth cysteines found in other Chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most Chemokine Receptors are able to bind multiple high-affinity Chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most Chemokines bind to more than one receptor subtype. Receptors for inflammatory Chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled Chemokine Receptors are named acccording to the class of Chemokines bound, whereas ACKR is the root acronym for atypical Chemokine Receptors [33]. There can be substantial cross-species differences in the sequences of both Chemokines and Chemokine Receptors, and in the pharmacology and biology of Chemokine Receptors. Endogenous and microbial non-Chemokine ligands have also been identified for Chemokine Receptors. Many Chemokine Receptors function as HIV co-Receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard Chemokine receptor names [675] and aliases.
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international union of pharmacology lxxxix update on the extended family of Chemokine Receptors and introducing a new nomenclature for atypical Chemokine Receptors
Pharmacological Reviews, 2014Co-Authors: Francoise Bachelerie, Massimo Locati, Gerard J. Graham, Adit Benbaruch, Richard Horuk, Amanda M Burkhardt, Christophe Combadiere, Joshua M Farber, Alexander Hovard Sparreulrich, Andrew D LusterAbstract:Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled Chemokine Receptors, the large family of leukocyte chemoattractant Receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since then, several new Receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at Chemokine Receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical Chemokine Receptors has emerged that may signal through arrestins instead of G proteins to act as Chemokine scavengers, and many microbial and invertebrate G protein-coupled Chemokine Receptors and soluble Chemokine-binding proteins have been described. Here, we review this extended family of Chemokine Receptors and Chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical Chemokine Receptors with the stem ACKR (atypical Chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.
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immune regulation by atypical Chemokine Receptors
Nature Reviews Immunology, 2013Co-Authors: Robert J B Nibbs, Gerard J. GrahamAbstract:Chemokines have fundamental roles in regulating immune and inflammatory responses, primarily through their control of leukocyte migration and localization. The biological functions of Chemokines are typically mediated by signalling through G protein-coupled Chemokine Receptors, but Chemokines are also bound by a small family of atypical Chemokine Receptors (ACKRs), the members of which are unified by their inability to initiate classical signalling pathways after ligand binding. These ACKRs are emerging as crucial regulatory components of Chemokine networks in a wide range of developmental, physiological and pathological contexts. In this Review, we discuss the biochemical and immunological properties of ACKRs and the potential unifying themes in this family, and we highlight recent studies that identify novel roles for these molecules in development , homeostasis, inflammatory disease, infection and cancer.
Marek Honczarenko - One of the best experts on this subject based on the ideXlab platform.
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human bone marrow stromal cells express a distinct set of biologically functional Chemokine Receptors
Stem Cells, 2006Co-Authors: Marek Honczarenko, Yi Le, Marcin Swierkowski, Aleksandra M Glodek, Ionita Ghiran, E Leslie M D SilbersteinAbstract:Stromal cells isolated from bone marrow (BMSCs), often referred to as mesenchymal stem cells, are currently under investigation for a variety of therapeutic applications. However, limited data are available regarding Receptors that can influence their homing to and positioning within the bone marrow. In the present study, we found that second passage BMSCs express a unique set of Chemokine Receptors: three CC Chemokine Receptors (CCR1, CCR7, and CCR9) and three CXC Chemokine Receptors (CXCR4, CXCR5, and CXCR6). BMSCs cultured in serum-free medium secrete several Chemokine ligands (CCL2, CCL4, CCL5, CCL20, CXCL12, CXCL8, and CX3CL1). The surface-expressed Chemokine Receptors were functional by several criteria. Stimulation of BMSCs with Chemokine ligands triggers phosphorylation of the mitogen-activated protein kinase (e.g., extracellular signal–related kinase [ERK]-1 and ERK-2) and focal adhesion kinase signaling pathways. In addition, CXCL12 selectively activates signal transducer and activator of transcription (STAT)-5 whereas CCL5 activates STAT-1. In cell biologic assays, all of the Chemokines tested stimulate chemotaxis of BMSCs, and CXCL12 induces cytoskeleton F-actin polymerization. Studies of culture-expanded BMSCs, for example, 12–16 passages, indicate loss of surface expression of all Chemokine Receptors and lack of chemotactic response to Chemokines. The loss in Chemokine receptor expression is accompanied by a decrease in expression of adhesion molecules (ICAM-1, ICAM-2, and vascular cell adhesion molecule 1) and CD157, while expression of CD90 and CD105 is maintained. The change in BMSC phenotype is associated with slowing of cell growth and increased spontaneous apoptosis. These findings suggest that several Chemokine axes may operate in BMSC biology and may be important parameters in the validation of cultured BMSCs intended for cell therapy.
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human bone marrow stromal cells express a distinct set of biologically functional Chemokine Receptors
Stem Cells, 2006Co-Authors: Marek Honczarenko, Yi Le, Marcin Swierkowski, Aleksandra M Glodek, Ionita Ghiran, E Leslie M D SilbersteinAbstract:Stromal cells isolated from bone marrow (BMSCs), often referred to as mesenchymal stem cells, are currently under investigation for a variety of therapeutic applications. However, limited data are available regarding Receptors that can influence their homing to and positioning within the bone marrow. In the present study, we found that second passage BMSCs express a unique set of Chemokine Receptors: three CC Chemokine Receptors (CCR1, CCR7, and CCR9) and three CXC Chemokine Receptors (CXCR4, CXCR5, and CXCR6). BMSCs cultured in serum-free medium secrete several Chemokine ligands (CCL2, CCL4, CCL5, CCL20, CXCL12, CXCL8, and CX3CL1). The surface-expressed Chemokine Receptors were functional by several criteria. Stimulation of BMSCs with Chemokine ligands triggers phosphorylation of the mitogen-activated protein kinase (e.g., extracellular signal–related kinase [ERK]-1 and ERK-2) and focal adhesion kinase signaling pathways. In addition, CXCL12 selectively activates signal transducer and activator of transcription (STAT)-5 whereas CCL5 activates STAT-1. In cell biologic assays, all of the Chemokines tested stimulate chemotaxis of BMSCs, and CXCL12 induces cytoskeleton F-actin polymerization. Studies of culture-expanded BMSCs, for example, 12–16 passages, indicate loss of surface expression of all Chemokine Receptors and lack of chemotactic response to Chemokines. The loss in Chemokine receptor expression is accompanied by a decrease in expression of adhesion molecules (ICAM-1, ICAM-2, and vascular cell adhesion molecule 1) and CD157, while expression of CD90 and CD105 is maintained. The change in BMSC phenotype is associated with slowing of cell growth and increased spontaneous apoptosis. These findings suggest that several Chemokine axes may operate in BMSC biology and may be important parameters in the validation of cultured BMSCs intended for cell therapy.
Raffaella Bonecchi - One of the best experts on this subject based on the ideXlab platform.
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Chemokines and Chemokine Receptors new targets for cancer immunotherapy
Frontiers in Immunology, 2019Co-Authors: Valeria Mollica Poeta, Matteo Massara, Arianna Capucetti, Raffaella BonecchiAbstract: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.
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Atypical Chemokine Receptors in cancer: friends or foes?
Journal of leukocyte biology, 2016Co-Authors: Matteo Massara, Massimo Locati, Alberto Mantovani, Ornella Bonavita, Raffaella BonecchiAbstract:The Chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical Chemokine Receptors are a new, emerging class of regulators of the Chemokine system. They control Chemokine bioavailability by scavenging, transporting, or storing Chemokines. They can also regulate the activity of canonical Chemokine Receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these Receptors (atypical Chemokine receptor 1/Duffy antigen receptor for Chemokine, atypical Chemokine receptor 2/D6, atypical Chemokine receptor 3/CXC-Chemokine receptor 7, and atypical Chemokine receptor 4/CC-Chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other Chemokine Receptors. Indeed, atypical Chemokine Receptors inhibit tumor growth and progression through their activity as negative regulators of Chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other Chemokine Receptors, such as CXC-Chemokine receptor 4. Thus, atypical Chemokine Receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies.
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Chemokine Receptors intracellular trafficking
Pharmacology & Therapeutics, 2010Co-Authors: Elena Monica Borroni, Massimo Locati, Alberto Mantovani, Raffaella BonecchiAbstract:Chemokines coordinate leukocyte recruitment during inflammatory and immune responses through the interaction with a distinct subfamily of G protein-coupled Receptors. The magnitude of the cellular response elicited by Chemokines is dictated by the level of receptor expression at the plasma membrane, which is the balance of finely tuned endocytic and recycling pathways. Recent data have revealed that receptor trafficking properties can drive Chemokine Receptors to lysosomal degradation or recycling pathways, producing opposite effects on the strength of the intracellular signaling cascade. This review will cover recent advances on the molecular mechanisms underlying Chemokine receptor internalization, recycling and degradation pathways, with particular attention to structural motifs present in receptor intracellular domains and their interacting adaptor proteins that modulate receptor trafficking and dictate proper biological response.
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selective up regulation of Chemokine Receptors ccr4 and ccr8 upon activation of polarized human type 2 th cells
Journal of Immunology, 1998Co-Authors: Daniele Dambrosio, Raffaella Bonecchi, Silvano Sozzani, Alberto Mantovani, Andrea Iellem, D Mazzeo, Francesco SinigagliaAbstract:Polarized Th1 and Th2 cells differentially express adhesion molecules and Chemokine Receptors, endowing these cells with distinct tissue homing capabilities. Here we report that, in contrast to other Chemokine Receptors, the expression of CCR4 and CCR8 on Th2 cells is transiently increased following TCR and CD28 engagement. IL-4 is not required for this activation-induced up-regulation of CCR4 and CCR8. In accordance with receptor expression, the response of Th2 cells to I-309 (CCR8 ligand) and thymus- and activation-regulated Chemokine (CCR4 and CCR8 ligand) is enhanced upon activation. Moreover, activated Th1 cells up-regulate CCR4 expression and functional responsiveness to thymus- and activation-regulated Chemokine. Analysis of polarized subsets of CD8+ T cells reveals a similar pattern of Chemokine receptor expression and modulation of responsiveness. Taken together, these findings suggest that an up-regulation of CCR4 and CCR8 following Ag encounter may contribute to the proper positioning of activated T cells within sites of antigenic challenge and/or specialized areas of lymphoid tissues.
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differential expression of Chemokine Receptors and chemotactic responsiveness of type 1 t helper cells th1s and th2s
Journal of Experimental Medicine, 1998Co-Authors: Raffaella Bonecchi, Silvano Sozzani, Giancarlo Bianchi, Paola Panina Bordignon, Daniele Dambrosio, Rosmarie Lang, Alessandro Borsatti, Paola Allavena, Patrick A Gray, Alberto MantovaniAbstract:T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases. The precise factors determining whether Th1- or Th2-mediated immune responses preferentially occur at a peripheral site of antigen exposure are largely unknown. Chemokines, a superfamily of polypeptide mediators, are a key component of the leukocyte recruitment process. Here we report that among four CXC (CXCR1-4) and five CC (CCR1-5) Chemokine Receptors analyzed, CXCR3 and CCR5 are preferentially expressed in human Th1s. In contrast, Th2s preferentially express CCR4 and, to a lesser extent, CCR3. In agreement with the differential Chemokine receptor expression, Th1s and Th2s selectively migrate in response to the corresponding Chemokines. The differential expression of Chemokine Receptors may dictate, to a large extent, the migration and tissue homing of Th1s and Th2s. It may also determine different susceptibility of Th1s and Th2s to human immunodeficiency virus strains using different fusion coReceptors.