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1
Hansell, C. A. H., C. V. Simpson, and R. J. B. Nibbs. "Chemokine sequestration by atypical chemokine receptors." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1009–13. http://dx.doi.org/10.1042/bst0341009.
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Leucocyte migration is essential for robust immune and inflammatory responses, and plays a critical role in many human diseases. Chemokines, a family of small secreted protein chemoattractants, are of fundamental importance in this process, directing leucocyte trafficking by signalling through heptahelical G-protein-coupled receptors expressed by the migrating cells. However, several mammalian chemokine receptors, including D6 and CCX-CKR (ChemoCentryx chemokine receptor), do not fit existing models of chemokine receptor function, and do not even appear to signal in response to chemokine binding. Instead, these ‘atypical’ chemokine receptors are biochemically specialized for chemokine sequestration, acting to regulate chemokine bioavailability and thereby influence responses through signalling-competent chemokine receptors. This is of critical importance in vivo, as mice lacking D6 show exaggerated cutaneous inflammatory responses and an increased susceptibility to the development of skin cancer. CCX-CKR, on the other hand, is predicted to modulate homoeostatic lymphocyte and dendritic cell trafficking, key migratory events in acquired immune responses that are directed by CCX-CKR-binding chemokines. Thus studies on ‘atypical’ chemokine receptors are revealing functional and biochemical diversity within the chemokine receptor family and providing insights into novel mechanisms of chemokine regulation.
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Borroni, Elena M., Raffaella Bonecchi, and Annalisa M. VanHook. "Science Signaling Podcast: 30 April 2013." Science Signaling 6, no. 273 (April 30, 2013): pc11. http://dx.doi.org/10.1126/scisignal.2004231.
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This Podcast features an interview with Elena M. Borroni and Raffaella Bonecchi, authors of a Research Article that appears in the 30 April 2013 issue of Science Signaling. Chemokines recruit leukocytes to sites of infection and inflammation by binding to chemokine receptors, which are members of the G protein–coupled receptor superfamily, present on the surface of leukocytes. Whereas activation of typical chemokine receptors leads to G protein–dependent signaling that promotes cell migration toward the chemokine source, activation of atypical chemokine receptors does not promote cell migration. Instead, signaling initiated by atypical chemokine receptors contributes to the immune response in other ways. The atypical chemokine receptor D6 is a scavenger that alters the chemokine gradient by binding to and degrading chemokines. Borroni and Bonecchi found that activation of a β-arrestin–dependent signaling pathway was necessary for D6 to act as a chemokine scavenger.
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Groblewska, Magdalena, Ala Litman-Zawadzka, and Barbara Mroczko. "The Role of Selected Chemokines and Their Receptors in the Development of Gliomas." International Journal of Molecular Sciences 21, no. 10 (May 24, 2020): 3704. http://dx.doi.org/10.3390/ijms21103704.
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Among heterogeneous primary tumors of the central nervous system (CNS), gliomas are the most frequent type, with glioblastoma multiforme (GBM) characterized with the worst prognosis. In their development, certain chemokine/receptor axes play important roles and promote proliferation, survival, metastasis, and neoangiogenesis. However, little is known about the significance of atypical receptors for chemokines (ACKRs) in these tumors. The objective of the study was to present the role of chemokines and their conventional and atypical receptors in CNS tumors. Therefore, we performed a thorough search for literature concerning our investigation via the PubMed database. We describe biological functions of chemokines/chemokine receptors from various groups and their significance in carcinogenesis, cancer-related inflammation, neo-angiogenesis, tumor growth, and metastasis. Furthermore, we discuss the role of chemokines in glioma development, with particular regard to their function in the transition from low-grade to high-grade tumors and angiogenic switch. We also depict various chemokine/receptor axes, such as CXCL8-CXCR1/2, CXCL12-CXCR4, CXCL16-CXCR6, CX3CL1-CX3CR1, CCL2-CCR2, and CCL5-CCR5 of special importance in gliomas, as well as atypical chemokine receptors ACKR1-4, CCRL2, and PITPMN3. Additionally, the diagnostic significance and usefulness of the measurement of some chemokines and their receptors in the blood and cerebrospinal fluid (CSF) of glioma patients is also presented.
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Ulvmar, Maria Helena, Elin Hub, and Antal Rot. "Atypical chemokine receptors." Experimental Cell Research 317, no. 5 (March 2011): 556–68. http://dx.doi.org/10.1016/j.yexcr.2011.01.012.
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Gencer, Selin, Emiel van der Vorst, Maria Aslani, Christian Weber, Yvonne Döring, and Johan Duchene. "Atypical Chemokine Receptors in Cardiovascular Disease." Thrombosis and Haemostasis 119, no. 04 (February 4, 2019): 534–41. http://dx.doi.org/10.1055/s-0038-1676988.
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AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.
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Legler, Daniel F., and Marcus Thelen. "New insights in chemokine signaling." F1000Research 7 (January 23, 2018): 95. http://dx.doi.org/10.12688/f1000research.13130.1.
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Chemokine signaling is essential for coordinated cell migration in health and disease to specifically govern cell positioning in space and time. Typically, chemokines signal through heptahelical, G protein-coupled receptors to orchestrate cell migration. Notably, chemokine receptors are highly dynamic structures and signaling efficiency largely depends on the discrete contact with the ligand. Promiscuity of both chemokines and chemokine receptors, combined with biased signaling and allosteric modulation of receptor activation, guarantees a tightly controlled recruitment and positioning of individual cells within the local environment at a given time. Here, we discuss recent insights in understanding chemokine gradient formation by atypical chemokine receptors and how typical chemokine receptors can transmit distinct signals to translate guidance cues into coordinated cell locomotion in space and time.
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Gustavsson, Martin, Douglas P. Dyer, Chunxia Zhao, and Tracy M. Handel. "Kinetics of CXCL12 binding to atypical chemokine receptor 3 reveal a role for the receptor N terminus in chemokine binding." Science Signaling 12, no. 598 (September 10, 2019): eaaw3657. http://dx.doi.org/10.1126/scisignal.aaw3657.
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Chemokines bind to membrane-spanning chemokine receptors, which signal through G proteins and promote cell migration. However, atypical chemokine receptor 3 (ACKR3) does not appear to couple to G proteins, and instead of directly promoting cell migration, it regulates the extracellular concentration of chemokines that it shares with the G protein–coupled receptors (GPCRs) CXCR3 and CXCR4, thereby influencing the responses of these receptors. Understanding how these receptors bind their ligands is important for understanding these different processes. Here, we applied association and dissociation kinetic measurements coupled to β-arrestin recruitment assays to investigate ACKR3:chemokine interactions. Our results showed that CXCL12 binding is unusually slow and driven by the interplay between multiple binding epitopes. We also found that the amino terminus of the receptor played a key role in chemokine binding and activation by preventing chemokine dissociation. It was thought that chemokines initially bind receptors through interactions between the globular domain of the chemokine and the receptor amino terminus, which then guides the chemokine amino terminus into the transmembrane pocket of the receptor to initiate signaling. On the basis of our kinetic data, we propose an alternative mechanism in which the amino terminus of the chemokine initially forms interactions with the extracellular loops and transmembrane pocket of the receptor, which is followed by the receptor amino terminus wrapping around the core of the chemokine to prolong its residence time. These data provide insight into how ACKR3 competes and cooperates with canonical GPCRs in its function as a scavenger receptor.
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Pacheco, Messias Oliveira, Fernanda Agostini Rocha, Thiago Pinheiro Arrais Aloia, and Luciana Cavalheiro Marti. "Evaluation of Atypical Chemokine Receptor Expression in T Cell Subsets." Cells 11, no. 24 (December 16, 2022): 4099. http://dx.doi.org/10.3390/cells11244099.
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Chemokines are molecules that pertain to a family of small cytokines and can generate cell chemotaxis through the interaction with their receptors. Chemokines can trigger signaling via conventional G-protein-coupled receptors or through atypical chemokine receptors. Currently, four atypical chemokine receptors have been are described (ACKR1, ACKR2, ACKR3 and ACKR4). ACKRs are expressed in various cells and tissues, including T lymphocytes. These receptors’ main function is related to the internalization and degradation of chemokines, as well as to the inflammation control. However, the expression of these receptors in human T lymphocytes is unclear in the literature. The objective of this study was to evaluate the expression of ACKRs in different subpopulations of T lymphocytes. For this, peripheral blood from healthy donors was used to analyze the expression of ACKR2, ACKR3 and ACKR4 by immunophenotyping CD4, CD8 T lymphocytes and, in their subsets, naive, transition and memory. Results obtained in this study demonstrated that ACKR2, ACKR3 and ACKR4 receptors were expressed by T lymphocytes subsets in different proportions. These receptors are highly expressed in the cytoplasmic milieu of all subsets of T lymphocytes, therefore suggesting that their expression in plasma membrane is regulated after transcription, and it must be dependent on a stimulus, which was not identified in our study. Thus, regarding ACKRs function as scavenger receptors, at least for the ACKR3, this function does not impair the chemotaxis exert for their ligand compared to the typical counterpart receptor.
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Miyabe, Yoshishige, Chie Miyabe, Vinidhra Mani, Thorsten R. Mempel, and Andrew D. Luster. "Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation." Science Immunology 4, no. 35 (May 10, 2019): eaav5951. http://dx.doi.org/10.1126/sciimmunol.aav5951.
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Chemoattractant-induced arrest of circulating leukocytes and their subsequent diapedesis is a fundamental component of inflammation. However, how tissue-derived chemoattractants are transported into the blood vessel lumen to induce leukocyte entry into tissue is not well understood. Here, intravital microscopy in live mice has shown that the “atypical” complement C5a receptor 2 (C5aR2) and the atypical chemokine receptor 1 (ACKR1) expressed on endothelial cells were required for the transport of C5a and CXCR2 chemokine ligands, respectively, into the vessel lumen in a murine model of immune complex–induced arthritis. Transported C5a was required to initiate C5aR1-mediated neutrophil arrest, whereas transported chemokines were required to initiate CXCR2-dependent neutrophil transdendothelial migration. These findings provide new insights into how atypical chemoattractant receptors collaborate with “classical” signaling chemoattractant receptors to control distinct steps in the recruitment of neutrophils into tissue sites of inflammation.
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Leick, Marion, Julie Catusse, and Meike Burger. "The Atypical Chemokine Receptor CRAM Mediates CCL19 Transcytosis through Endothelial Cells and Modulates CCL19 Activation of Non-Hodgkin Lymphoma B Cells." Blood 114, no. 22 (November 20, 2009): 2672. http://dx.doi.org/10.1182/blood.v114.22.2672.2672.
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Abstract Abstract 2672 Poster Board II-648 Introduction: Chemokines work as cellular recruitment molecules. Specific combinations of chemokines, receptors, and adhesion molecules determine which subgroups of leukocytes migrate and what their destinations are. Chemokine receptor expression and activation on malignant cells may be involved in the growth, survival and migration of cancer cells as well as in the tumor vascularisation. CCR7, by binding the chemokines CCL19 and CCL21, is centrally involved in B cell localisation to the secondary lymphoid organs and therefore implicated in lymphadenopathy of various non-hodgkin lymphomas (NHL). In addition to chemokine receptors that have been cloned and described, various orphan receptors with a chemokine receptor-like structure are still not characterized. Atypical, non-signaling chemokine receptors are members of a newly described class of receptors and have been implicated with chemokine clearance and influencing of other signalling receptors. They are consequently considered as potent immuno-modulators and as anti-inflammatory factors and are implicated in progression of cancer. Among these receptors, we are investigating the role of the orphan chemokine (C-C motif) receptor-like 2 (CCRL2), also known as CRAM, a receptor expressed on endothelial cells and B cells in a maturation stage dependent manner, but for which functions and ligands are poorly characterized so far. In an effort to elucidate the role of CRAM and its implication in neoplasias, we have focussed research on identification of ligands and the implication of CRAM in regulating B cell migration in samples from healthy donors and from non-Hodgkin lymphomas. Methods: We characterised the receptor's expression profile by flow cytometry in peripheral blood, bone marrow and lymph node sections of different B cell NHL and correlated it to expression levels of CCR7 and CXCR4. In addition, a screening for ligands was performed using radiolabelled binding assays. The role of CRAM was elucidated using various functional assays, internalisation and transcytosis experiments. Results: We show that CRAM is an alternative, but non-signaling receptor for the CCR7-activating chemokine CCL19. CRAM is constitutively recycling to and from the cell surface and internalizing the chemokine without degrading it. We found that the receptor is responsible for transcytosis of CCL19 through endothelial cell layers and subsequent presentation, a crucial step in homing of leukocytes to the lymph nodes. On the other hand, when expressed on B cells, CRAM interferes in CCL19 binding to CCR7. We thereby show that CRAM can act as an integrator of different signals, by binding different chemokines and controlling their activity toward surrounding ligands. Chemotaxis experiments demonstrate that CRAM is a negative modulator of CCL19 B cell recruitment. In addition, we have found increased expression in activated B cells, dendritic cells, and also in the B cell malignancies chronic lymphocytic leukemia (B-CLL) and pre-B cell acute lymphoblastic leukemia (pre-B ALL), and are currently evaluating CRAM as a possible prognostic marker in various B-NHLs. Conclusions: CRAM is a newly identified member of the silent or atypical chemokine receptor group, already known for modulating chemokine availability, together with D6, DARC and CCX-CKR. We have shown here that it contributes to lymphocyte recruitment into peripheral lymphoid tissue by presenting CCL19 on endothelium. It is also involved in CCR7 driven recruitment of B cells by regulating CCL19 availability. Expression of CRAM differs in B cell malignancies for which both CCR7 ligands, CCL19 and CCL21, have already been shown to be implicated in the development of lymphadenopathies. We therefore suggest that CRAM is an additional player and potential biomarker in determining outcome and development of disease. Disclosures: No relevant conflicts of interest to declare.
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Samus, Maryna, and Antal Rot. "Atypical chemokine receptors in cancer." Cytokine 176 (April 2024): 156504. http://dx.doi.org/10.1016/j.cyto.2024.156504.
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Chevigné, Andy, Bassam Janji, Max Meyrath, Nathan Reynders, Giulia D’Uonnolo, Tomasz Uchański, Malina Xiao, et al. "CXCL10 Is an Agonist of the CC Family Chemokine Scavenger Receptor ACKR2/D6." Cancers 13, no. 5 (March 2, 2021): 1054. http://dx.doi.org/10.3390/cancers13051054.
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Atypical chemokine receptors (ACKRs) are important regulators of chemokine functions. Among them, the atypical chemokine receptor ACKR2 (also known as D6) has long been considered as a scavenger of inflammatory chemokines exclusively from the CC family. In this study, by using highly sensitive β-arrestin recruitment assays based on NanoBiT and NanoBRET technologies, we identified the inflammatory CXC chemokine CXCL10 as a new strong agonist ligand for ACKR2. CXCL10 is known to play an important role in the infiltration of immune cells into the tumour bed and was previously reported to bind to CXCR3 only. We demonstrated that ACKR2 is able to internalize and reduce the availability of CXCL10 in the extracellular space. Moreover, we found that, in contrast to CC chemokines, CXCL10 activity towards ACKR2 was drastically reduced by the dipeptidyl peptidase 4 (DPP4 or CD26) N-terminal processing, pointing to a different receptor binding pocket occupancy by CC and CXC chemokines. Overall, our study sheds new light on the complexity of the chemokine network and the potential role of CXCL10 regulation by ACKR2 in many physiological and pathological processes, including tumour immunology. Our data also testify that systematic reassessment of chemokine-receptor pairing is critically needed as important interactions may remain unexplored.
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Blanchet, Xavier, Christian Weber, and Philipp von Hundelshausen. "Chemokine Heteromers and Their Impact on Cellular Function—A Conceptual Framework." International Journal of Molecular Sciences 24, no. 13 (June 30, 2023): 10925. http://dx.doi.org/10.3390/ijms241310925.
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Chemoattractant cytokines or chemokines are proteins involved in numerous biological activities. Their essential role consists of the formation of gradient and (immune) cell recruitment. Chemokine biology and its related signaling system is more complex than simple ligand–receptor interactions. Beside interactions with their cognate and/or atypical chemokine receptors, and glycosaminoglycans (GAGs), chemokines form complexes with themselves as homo-oligomers, heteromers and also with other soluble effector proteins, including the atypical chemokine MIF, carbohydrate-binding proteins (galectins), damage-associated molecular patterns (DAMPs) or with chemokine-binding proteins such as evasins. Likewise, nucleic acids have been described as binding targets for the tetrameric form of CXCL4. The dynamic balance between monomeric and dimeric structures, as well as interactions with GAGs, modulate the concentrations of free chemokines available along with the nature of the gradient. Dimerization of chemokines changes the canonical monomeric fold into two main dimeric structures, namely CC- and CXC-type dimers. Recent studies highlighted that chemokine dimer formation is a frequent event that could occur under pathophysiological conditions. The structural changes dictated by chemokine dimerization confer additional biological activities, e.g., biased signaling. The present review will provide a short overview of the known functionality of chemokines together with the consequences of the interactions engaged by the chemokines with other proteins. Finally, we will present potential therapeutic tools targeting the chemokine multimeric structures that could modulate their biological functions.
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Borroni, Elena M., Cinzia Cancellieri, Alessandro Vacchini, Yann Benureau, Bernard Lagane, Françoise Bachelerie, Fernando Arenzana-Seisdedos, et al. "β-Arrestin–Dependent Activation of the Cofilin Pathway Is Required for the Scavenging Activity of the Atypical Chemokine Receptor D6." Science Signaling 6, no. 273 (April 30, 2013): ra30. http://dx.doi.org/10.1126/scisignal.2003627.
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Chemokines promote the recruitment of leukocytes to sites of infection and inflammation by activating conventional heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). Chemokines are also recognized by a set of atypical chemokine receptors (ACRs), which cannot induce directional cell migration but are required for the generation of chemokine gradients in tissues. ACRs are presently considered “silent receptors” because no G protein–dependent signaling activity is observed after their engagement by cognate ligands. We report that engagement of the ACR D6 by its ligands activates a β-arrestin1–dependent, G protein–independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin through the Rac1–p21-activated kinase 1 (PAK1)–LIM kinase 1 (LIMK1) cascade. This signaling pathway is required for the increased abundance of D6 protein at the cell surface and for its chemokine-scavenging activity. We conclude that D6 is a signaling receptor that exerts its regulatory function on chemokine-mediated responses in inflammation and immunity through a distinct signaling pathway.
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Melgrati, Serena, Egle Radice, Rafet Ameti, Elin Hub, Sylvia Thelen, Pawel Pelczar, David Jarrossay, Antal Rot, and Marcus Thelen. "Atlas of the anatomical localization of atypical chemokine receptors in healthy mice." PLOS Biology 21, no. 5 (May 9, 2023): e3002111. http://dx.doi.org/10.1371/journal.pbio.3002111.
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Atypical chemokine receptors (ACKRs) scavenge chemokines and can contribute to gradient formation by binding, internalizing, and delivering chemokines for lysosomal degradation. ACKRs do not couple to G-proteins and fail to induce typical signaling induced by chemokine receptors. ACKR3, which binds and scavenges CXCL12 and CXCL11, is known to be expressed in vascular endothelium, where it has immediate access to circulating chemokines. ACKR4, which binds and scavenges CCL19, CCL20, CCL21, CCL22, and CCL25, has also been detected in lymphatic and blood vessels of secondary lymphoid organs, where it clears chemokines to facilitate cell migration. Recently, GPR182, a novel ACKR-like scavenger receptor, has been identified and partially deorphanized. Multiple studies point towards the potential coexpression of these 3 ACKRs, which all interact with homeostatic chemokines, in defined cellular microenvironments of several organs. However, an extensive map of ACKR3, ACKR4, and GPR182 expression in mice has been missing. In order to reliably detect ACKR expression and coexpression, in the absence of specific anti-ACKR antibodies, we generated fluorescent reporter mice, ACKR3GFP/+, ACKR4GFP/+, GPR182mCherry/+, and engineered fluorescently labeled ACKR-selective chimeric chemokines for in vivo uptake. Our study on young healthy mice revealed unique and common expression patterns of ACKRs in primary and secondary lymphoid organs, small intestine, colon, liver, and kidney. Furthermore, using chimeric chemokines, we were able to detect distinct zonal expression and activity of ACKR4 and GPR182 in the liver, which suggests their cooperative relationship. This study provides a broad comparative view and a solid stepping stone for future functional explorations of ACKRs based on the microanatomical localization and distinct and cooperative roles of these powerful chemokine scavengers.
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Schlecht-Louf, Géraldine, Claire Deback, and Françoise Bachelerie. "The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy." Cancers 14, no. 3 (February 8, 2022): 848. http://dx.doi.org/10.3390/cancers14030848.
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Chemokines interact with glycosaminoglycans of the extracellular matrix and activate heptahelical cellular receptors that mainly consist of G Protein-Coupled Receptors and a few atypical receptors also with decoy activity. They are well-described targets of oncogenic pathways and key players in cancer development, invasiveness, and metastasis acting both at the level of cancer cells and cells of the tumor microenvironment. Hence, they can regulate cancer cell proliferation and survival and promote immune or endothelial cell migration into the tumor microenvironment. Additionally, oncogenic viruses display the potential of jeopardizing the chemokine system by encoding mimics of chemokines and receptors as well as several products such as oncogenic proteins or microRNAs that deregulate their human host transcriptome. Conversely, the chemokine system participates in the host responses that control the virus life cycle, knowing that most oncoviruses establish asymptomatic latent infections. Therefore, the deregulated expression and function of chemokines and receptors as a consequence of acquired or inherited mutations could bias oncovirus infection toward pro-oncogenic pathways. We here review these different processes and discuss the anticancer therapeutic potential of targeting chemokine availability or receptor activation, from signaling to decoy-associated functions, in combination with immunotherapies.
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Patel, Manish, Iain McInnes, and Gerard Graham. "Atypical Chemokine Receptors in Inflammatory Disease." Current Molecular Medicine 9, no. 1 (February 1, 2009): 86–93. http://dx.doi.org/10.2174/156652409787314480.
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Segerer, Stephan, Jan Jedlicka, and Rudolf P. Wüthrich. "Atypical Chemokine Receptors in Renal Inflammation." Nephron Experimental Nephrology 115, no. 4 (2010): e89-e95. http://dx.doi.org/10.1159/000313489.
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Bachelerie, Françoise, Gerard J. Graham, Massimo Locati, Alberto Mantovani, Philip M. Murphy, Robert Nibbs, Antal Rot, Silvano Sozzani, and Marcus Thelen. "New nomenclature for atypical chemokine receptors." Nature Immunology 15, no. 3 (February 18, 2014): 207–8. http://dx.doi.org/10.1038/ni.2812.
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Nibbs, Robert J. B., and Gerard J. Graham. "Immune regulation by atypical chemokine receptors." Nature Reviews Immunology 13, no. 11 (October 11, 2013): 815–29. http://dx.doi.org/10.1038/nri3544.
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Purvanov, Vladimir, Christoph Matti, Guerric P. B. Samson, Ilona Kindinger, and Daniel F. Legler. "Fluorescently Tagged CCL19 and CCL21 to Monitor CCR7 and ACKR4 Functions." International Journal of Molecular Sciences 19, no. 12 (December 4, 2018): 3876. http://dx.doi.org/10.3390/ijms19123876.
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Chemokines are essential guidance cues orchestrating cell migration in health and disease. Cognate chemokine receptors sense chemokine gradients over short distances to coordinate directional cell locomotion. The chemokines CCL19 and CCL21 are essential for recruiting CCR7-expressing dendritic cells bearing pathogen-derived antigens and lymphocytes to lymph nodes, where the two cell types meet to launch an adaptive immune response against the invading pathogen. CCR7-expressing cancer cells are also recruited by CCL19 and CCL21 to metastasize in lymphoid organs. In contrast, atypical chemokine receptors (ACKRs) do not transmit signals required for cell locomotion but scavenge chemokines. ACKR4 is crucial for internalizing and degrading CCL19 and CCL21 to establish local gradients, which are sensed by CCR7-expressing cells. Here, we describe the production of fluorescently tagged chemokines by fusing CCL19 and CCL21 to monomeric red fluorescent protein (mRFP). We show that purified CCL19-mRFP and CCL21-mRFP are versatile and powerful tools to study CCR7 and ACKR4 functions, such as receptor trafficking and chemokine scavenging, in a spatiotemporal fashion. We demonstrate that fluorescently tagged CCL19 and CCL21 permit the visualization and quantification of chemokine gradients in real time, while CCR7-expressing leukocytes and cancer cells sense the guidance cues and migrate along the chemokine gradients.
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Cancellieri, Cinzia, Alessandro Vacchini, Massimo Locati, Raffaella Bonecchi, and Elena M. Borroni. "Atypical chemokine receptors: from silence to sound." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 231–36. http://dx.doi.org/10.1042/bst20120246.
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ACRs (atypical chemokine receptors) were initially referred to as ‘silent’ receptors on the basis of a lack of signalling and functional activities that are typically observed with conventional chemokine receptors. Although ACRs do not directly induce cell migration, they indirectly control leucocyte recruitment by shaping chemokine gradients in tissues through degradation, transcytosis or local concentration of their cognate ligands. Recent evidence also suggests that these biological activities are supported by G-protein-independent, β-arrestin-dependent signalling events. In the present article, we review current knowledge on structural and signalling properties of ACRs that are changing our view on this entire class of receptors from silent to endogenous β-arrestin-biased signalling receptors.
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Tsou, Chia-Lin, Ron P. Gladue, Laurie A. Carroll, Tim Paradis, James G. Boyd, Robin T. Nelson, Kuldeep Neote, and Israel F. Charo. "Identification of C-C Chemokine Receptor 1 (CCR1) as the Monocyte Hemofiltrate C-C Chemokine (HCC)-1 Receptor." Journal of Experimental Medicine 188, no. 3 (August 3, 1998): 603–8. http://dx.doi.org/10.1084/jem.188.3.603.
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Hemofiltrate C-C chemokine (HCC)-1 is a recently cloned C-C chemokine that is structurally similar to macrophage inflammatory protein (MIP)-1α. Unlike most chemokines, it is constitutively secreted by tissues and is present at high concentrations in normal human plasma. Also atypical for chemokines, HCC-1 is reported not to be chemotactic for leukocytes. In this paper, we have investigated the chemokine receptor usage and downstream signaling pathways of HCC-1. Cross-desensitization experiments using THP-1 cells suggested that HCC-1 and MIP-1α activated the same receptor. Experiments using a panel of cloned chemokine receptors revealed that HCC-1 specifically activated C-C chemokine receptor (CCR)1, but not closely related receptors, including CCR5. HCC-1 competed with MIP-1α for binding to CCR1-transfected cells, but with a markedly reduced affinity (IC50 = 93 nM versus 1.3 nM for MIP-1α). Similarly, HCC-1 was less potent than MIP-1α in inducing inhibition of adenylyl cyclase in CCR1-transfected cells. HCC-1 induced chemotaxis of freshly isolated human monocytes, THP-1 cells, and CCR1-transfected cells, and the optimal concentration for cell migration (100 nM) was ∼100-fold lower than that of MIP-1α (1 nM). These data demonstrate that HCC-1 is a chemoattractant and identify CCR1 as a functional HCC-1 receptor on human monocytes.
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Mackie, Duncan I., Natalie R. Nielsen, Matthew Harris, Smriti Singh, Reema B. Davis, Danica Dy, Graham Ladds, and Kathleen M. Caron. "RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis." Proceedings of the National Academy of Sciences 116, no. 48 (November 11, 2019): 24093–99. http://dx.doi.org/10.1073/pnas.1905561116.
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Receptor-activity–modifying proteins (RAMPs) are single transmembrane-spanning proteins which serve as molecular chaperones and allosteric modulators of G-protein–coupled receptors (GPCRs) and their signaling pathways. Although RAMPs have been previously studied in the context of their effects on Family B GPCRs, the coevolution of RAMPs with many GPCR families suggests an expanded repertoire of potential interactions. Using bioluminescence resonance energy transfer-based and cell-surface expression approaches, we comprehensively screen for RAMP interactions within the chemokine receptor family and identify robust interactions between RAMPs and nearly all chemokine receptors. Most notably, we identify robust RAMP interaction with atypical chemokine receptors (ACKRs), which function to establish chemotactic gradients for directed cell migration. Specifically, RAMP3 association with atypical chemokine receptor 3 (ACKR3) diminishes adrenomedullin (AM) ligand availability without changing G-protein coupling. Instead, RAMP3 is required for the rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following either AM or SDF-1/CXCL12 binding, thereby enabling formation of dynamic spatiotemporal chemotactic gradients. Consequently, genetic deletion of either ACKR3 or RAMP3 in mice abolishes directed cell migration of retinal angiogenesis. Thus, RAMP association with chemokine receptor family members represents a molecular interaction to control receptor signaling and trafficking properties.
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Khare, Tripti, Marc Bissonnette, and Sharad Khare. "CXCL12-CXCR4/CXCR7 Axis in Colorectal Cancer: Therapeutic Target in Preclinical and Clinical Studies." International Journal of Molecular Sciences 22, no. 14 (July 9, 2021): 7371. http://dx.doi.org/10.3390/ijms22147371.
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Chemokines are chemotactic cytokines that promote cancer growth, metastasis, and regulate resistance to chemotherapy. Stromal cell-derived factor 1 (SDF1) also known as C-X-C motif chemokine 12 (CXCL12), a prognostic factor, is an extracellular homeostatic chemokine that is the natural ligand for chemokine receptors C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD184) and chemokine receptor type 7 (CXCR7). CXCR4 is the most widely expressed rhodopsin-like G protein coupled chemokine receptor (GPCR). The CXCL12–CXCR4 axis is involved in tumor growth, invasion, angiogenesis, and metastasis in colorectal cancer (CRC). CXCR7, recently termed as atypical chemokine receptor 3 (ACKR3), is amongst the G protein coupled cell surface receptor family that is also commonly expressed in a large variety of cancer cells. CXCR7, like CXCR4, regulates immunity, angiogenesis, stem cell trafficking, cell growth and organ-specific metastases. CXCR4 and CXCR7 are expressed individually or together, depending on the tumor type. When expressed together, CXCR4 and CXCR7 can form homo- or hetero-dimers. Homo- and hetero-dimerization of CXCL12 and its receptors CXCR4 and CXCR7 alter their signaling activity. Only few drugs have been approved for clinical use targeting CXCL12-CXCR4/CXCR7 axis. Several CXCR4 inhibitors are in clinical trials for solid tumor treatment with limited success whereas CXCR7-specific inhibitors are still in preclinical studies for CRC. This review focuses on current knowledge of chemokine CXCL12 and its receptors CXCR4 and CXCR7, with emphasis on targeting the CXCL12–CXCR4/CXCR7 axis as a treatment strategy for CRC.
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Lindsay, Hunter G., Colby J. Hendrix, Josue D. Gonzalez Murcia, Christopher Haynie, and K. Scott Weber. "The Role of Atypical Chemokine Receptors in Neuroinflammation and Neurodegenerative Disorders." International Journal of Molecular Sciences 24, no. 22 (November 18, 2023): 16493. http://dx.doi.org/10.3390/ijms242216493.
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Neuroinflammation is associated with several neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Neuroinflammation provides protection in acute situations but results in significant damage to the nervous system if chronic. Overexpression of chemokines within the brain results in the recruitment and activation of glial and peripheral immune cells which can propagate a cascading inflammatory response, resulting in neurodegeneration and the onset of neurodegenerative disorders. Recent work has identified the role of atypical chemokine receptors (ACKRs) in neurodegenerative conditions. ACKRs are seven-transmembrane domain receptors that do not follow canonical G protein signaling, but regulate inflammatory responses by modulating chemokine abundance, location, and availability. This review summarizes what is known about the four ACKRs and three putative ACKRs within the brain, highlighting their known expression and discussing the current understanding of each ACKR in the context of neurodegeneration. The ability of ACKRs to alter levels of chemokines makes them an appealing therapeutic target for neurodegenerative conditions. However, further work is necessary to understand the expression of several ACKRs within the neuroimmune system and the effectiveness of targeted drug therapies in the prevention and treatment of neurodegenerative conditions.
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Eller, Kathrin, and Alexander R. Rosenkranz. "Atypical chemokine receptors—“chemokine PACMANs” as new therapeutic targets in glomerulonephritis." Kidney International 93, no. 4 (April 2018): 774–75. http://dx.doi.org/10.1016/j.kint.2017.12.021.
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Dragan, Paulina, Matthew Merski, Szymon Wiśniewski, Swapnil Ganesh Sanmukh, and Dorota Latek. "Chemokine Receptors—Structure-Based Virtual Screening Assisted by Machine Learning." Pharmaceutics 15, no. 2 (February 3, 2023): 516. http://dx.doi.org/10.3390/pharmaceutics15020516.
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Chemokines modulate the immune response by regulating the migration of immune cells. They are also known to participate in such processes as cell–cell adhesion, allograft rejection, and angiogenesis. Chemokines interact with two different subfamilies of G protein-coupled receptors: conventional chemokine receptors and atypical chemokine receptors. Here, we focused on the former one which has been linked to many inflammatory diseases, including: multiple sclerosis, asthma, nephritis, and rheumatoid arthritis. Available crystal and cryo-EM structures and homology models of six chemokine receptors (CCR1 to CCR6) were described and tested in terms of their usefulness in structure-based drug design. As a result of structure-based virtual screening for CCR2 and CCR3, several new active compounds were proposed. Known inhibitors of CCR1 to CCR6, acquired from ChEMBL, were used as training sets for two machine learning algorithms in ligand-based drug design. Performance of LightGBM was compared with a sequential Keras/TensorFlow model of neural network for these diverse datasets. A combination of structure-based virtual screening with machine learning allowed to propose several active ligands for CCR2 and CCR3 with two distinct compounds predicted as CCR3 actives by all three tested methods: Glide, Keras/TensorFlow NN, and LightGBM. In addition, the performance of these three methods in the prediction of the CCR2/CCR3 receptor subtype selectivity was assessed.
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Bryce, Steven, Andrew Luster, Gerry Graham, and Rob Nibbs. "The ‘atypical’ chemokine receptor CCRL1 aids dendritic cell migration from inflamed skin. (P6352)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 199.2. http://dx.doi.org/10.4049/jimmunol.190.supp.199.2.
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Abstract Chemokine-directed leukocyte migration is essential for immune and inflammatory responses. The chemokine receptor CCR7, by responding to chemokines CCL19 and CCL21, is critical in regulating the recruitment of dendritic cells (DC), from peripheral tissues to draining lymph nodes (LNs). CCR7 is required for DC entry into lymphatic vessels, and for the passage of these cells across subcapsular sinus of the lymph node. Here, they initiate adaptive immune responses by priming antigen-specific T cells. CCRL1, an unexpected second receptor for CCL19 and CCL21, belongs to the family of atypical chemokine receptors and is able to bind and sequester extracellular chemokine without exhibiting any form of classical chemokine signaling. CCRL1 function in vivo is still unclear. We have generated CCRL1 deficient mice but find no perturbations in DC numbers in the LNs at rest, and DC trafficking from the skin is normal after painting with hapten (FITC). However, if FITC is applied after the induction of cutaneous inflammation, FITC+ DCs fail to reach draining LNs. Using a combination of microscopy and flow cytometry, we show that DCs are unable to enter lymphatic vessels and remain trapped in the skin. These data will be presented in the context of new insights into the identity of CCRL1-expressing cells in the skin and lymph node. Collectively, our data indicate that CCRL1-mediated regulation of CCL19 and/or CCL21 is required to maintain DC departure from the skin during inflammation.
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Massara, Matteo, Ornella Bonavita, Alberto Mantovani, Massimo Locati, and Raffaella Bonecchi. "Atypical chemokine receptors in cancer: friends or foes?" Journal of Leukocyte Biology 99, no. 6 (February 23, 2016): 927–33. http://dx.doi.org/10.1189/jlb.3mr0915-431rr.
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Le Mercier, Alan, Remy Bonnavion, Weijia Yu, Mohamad Wessam Alnouri, Sophie Ramas, Yang Zhang, Yannick Jäger, et al. "GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis." Proceedings of the National Academy of Sciences 118, no. 17 (April 19, 2021): e2021596118. http://dx.doi.org/10.1073/pnas.2021596118.
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G protein–coupled receptor 182 (GPR182) has been shown to be expressed in endothelial cells; however, its ligand and physiological role has remained elusive. We found GPR182 to be expressed in microvascular and lymphatic endothelial cells of most organs and to bind with nanomolar affinity the chemokines CXCL10, CXCL12, and CXCL13. In contrast to conventional chemokine receptors, binding of chemokines to GPR182 did not induce typical downstream signaling processes, including Gq- and Gi-mediated signaling or β-arrestin recruitment. GPR182 showed relatively high constitutive activity in regard to β-arrestin recruitment and rapidly internalized in a ligand-independent manner. In constitutive GPR182-deficient mice, as well as after induced endothelium-specific loss of GPR182, we found significant increases in the plasma levels of CXCL10, CXCL12, and CXCL13. Global and induced endothelium-specific GPR182-deficient mice showed a significant decrease in hematopoietic stem cells in the bone marrow as well as increased colony-forming units of hematopoietic progenitors in the blood and the spleen. Our data show that GPR182 is a new atypical chemokine receptor for CXCL10, CXCL12, and CXCL13, which is involved in the regulation of hematopoietic stem cell homeostasis.
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Martini, Rachel, Petros Nikolinakos, Jamie Hodgson, Brittany Jenkins, and Melissa Davis. "The role of atypical chemokine receptor-1 in breast cancer immune response." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23072-e23072. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23072.
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e23072 Background: Interactions between chemokines and their receptors can regulate anti-tumor response by influencing the migration of immune cells. Atypical Chemokine Receptor 1 (ACKR1/DARC), a genetically diverse transmembrane GPCR, acts as a decoy receptor for a variety of CXC and CC chemokines, including those with pro-malignant and pro-inflammatory effects, such as CCL2 and CXCL8 . The purpose of this study is to determine if the migration of tumor-associated immune cells is unique based on epithelial ACKR1 expression on breast cancer cells, and if this association is correlated to an increase in pro-malignant chemokines, survival, or race. Methods: Immunohistochemistry techniques were used to determine expression of ACKR1 on primary breast tumors, along with T-cells, B-cells, dendritic cells, and macrophages. Concentrations of pro-inflammatory chemokines in circulation were determined using a Luminex-based immunoassay. In silco analyses were performed to determine associations between ACKR1 tumor status, race, and survival. Finally, using human breast cancer cell lines and immunofluorescence techniques, co-localization between ACKR1 and pro-inflammatory chemokines was investigated. Results: Results from these tests indicate that there is differential infiltration of immune cell types in tumors expressing ACKR1, , which were not detected in ACKR1 negative tumors. Significantly increased circulating CCL2 and CXCL8 chemokine levels we also determined to be positively correlated with ACKR1 expression in primary breast tumors. Survival analyses showed a significantly increased relapse free survival in patients having tumors with high ACKR1 expression, while investigations into racial differences revealed a significant race effect, with Caucasians having higher ACKR1 levels on their tumors than African-Americans. Finally, co-localization between ACKR1 with CCL2 and CXCL8 is observed in cultured human breast cancer cells. Conclusions: tumors positively expressing ACKR1 to have a more favorable prognosis suggest that a role of ACKR1 on breast tumor cells is to sequester pro-inflammatory chemokines in the tumor microenvironment, recruiting a distinct subset of tumor-associated immune cells.
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Graham, G. J., M. Locati, A. Mantovani, A. Rot, and M. Thelen. "The biochemistry and biology of the atypical chemokine receptors." Immunology Letters 145, no. 1-2 (July 2012): 30–38. http://dx.doi.org/10.1016/j.imlet.2012.04.004.
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Majumdar, Shamik, Sergio M. Pontejo, Joseph Weaver, and Philip M. Murphy. "Ackr1-deficient mice are protected from lethal SARS-CoV-2 challenge." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 79.08. http://dx.doi.org/10.4049/jimmunol.210.supp.79.08.
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Abstract To date, there have been more than 613 million confirmed cases of COVID-19, with over 6 million deaths worldwide. In severe cases, the causative agent of the COVID-19, SARS-CoV-2, induces acute respiratory distress syndrome. To study the roles of chemokine pathways during COVID-19 pathogenesis, we performed an infection screen in mice deficient in chemokine ligands and receptors using the mouse-adapted strain of the virus. Weight loss and death were recorded for 2 weeks after infection of wild type mice, and mice genetically deficient for Ccr2, Ccr5, Ccr6, Cxcr3, Cxcr6, Cxcl10 or the atypical chemokine receptor Ackr1. Acute weight loss was observed in all infected mouse strains; however, Ackr1−/−mice uniquely displayed markedly increased survival compared to wild type mice. ACKR1 (also known as the Duffy antigen receptor for chemokines) is a non-signaling receptor expressed on endothelial cells, erythrocytes and a subset of neurons that binds to a wide range of chemokines thereby controlling their availability as a scavenger and shaping chemotactic gradients. Comprehensive expression analysis revealed Ackr1 as the most highly induced chemokine receptor in infected lung post-infection. Of note, COVID-19 mortality is disproportionately low in West Africa, overlapping with the geographic distribution of genetic deficiency of erythrocyte ACKR1 due to a single nucleotide polymorphism in the ACKR1 promoter that interrupts binding of GATA-1. Further studies are required to understand the modulation of SARS-CoV-2 pathogenesis by Ackr1 and its potential to explain the trajectory and limited mortality of Covid-19 in Africa and to serve as a potential therapeutic target.
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Johnsson, H., J. Cole, G. Wilson, M. Pingen, F. Mcmonagle, S. Holmes, I. Mcinnes, S. Siebert, and G. Graham. "SAT0351 CHEMOKINE PATHWAYS ARE ENRICHED IN PSORIATIC ARTHRITIS (PSA) SKIN LESIONS WITH INCREASED EXPRESSION OF ATYPICAL CHEMOKINE RECEPTOR 2 (ACKR2)." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1121.2–1122. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2980.
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Background:Skin in people with psoriasis has been comprehensively studied; uninvolved skin has abnormal gene expression. Less is known specifically about skin in PsA, the assumption being that it is identical to psoriasis. Chemokines and ACKR2 are among the upregulated genes in uninvolved psoriasis compared to healthy skin[1]. ACKR2 is a scavenging receptor of inflammatory CC chemokines and has been proposed as a regulator of cutaneous inflammation in psoriasis. It has not been studied in PsA.Objectives:To compare the transcriptome of PsA lesional, PsA uninvolved and healthy control skin and evaluate ACKR2 expression in PsA.Methods:Biopsies were taken from healthy control (HC) skin and paired lesional and uninvolved skin from patients with PsA. Libraries for bulk RNA sequencing were prepared from polyA selected RNA and sequenced on NovaSeq 6000. Sequencing data were analysed using Searchlight2. ACKR2 mRNA expression was validated by qPCR. RNAscope was used to localise ACKR2 expressing cells and sections were co-stained with podaplanin or stained in serial sections with CD45. Chemokine protein expression in skin was evaluated using Luminex technology.Results:Nine HC and 9 paired skin samples from patients with PsA were sequenced. The PsA skin lesions (PsA L) formed a distinct population in the transcriptomic principal component analysis (PCA) plot while HC and PsA uninvolved skin (PsA U) were overlapping. Only 15 genes were differentially expressed between HC and PsA U and none coded for chemokines. There were however significantly upregulated chemokines and receptors in PsA L. Unexpectely, ACKR2 was the 2ndmost upregulated chemokine receptor in PsA L with unchanged expression in PsA U compared with HC (PsA L vs HC log2fold 3.38, p.adj=9.51E-41; PsA L vs PsA U log2fold 3.58, p.adj=3.24E-45; PsA U vs HC log2fold -0.2, p.adj=0.732).The upregulation of ACKR2 in PsA L and unchanged expression in PsA U was confirmed by qPCR. RNAscope demonstrated strong expression of ACKR2 in the suprabasal layer of the epidermis in PsA L. In HC and PsA U, only occasional ACKR2 positive cells were seen in the epidermis. ACKR2 was expressed in lymphatic vessel walls but was not observed in CD45+ leukocytes.Provisional skin chemokine protein expression data showed poor correlation between mRNA levels and protein expression for the ACKR2 ligands CCL2, CCL3, CCL7, CCL8, CCL11, CCL13 and CCL22 in HC and PsA U, with negative correlation between ACKR2 mRNA expression and CCL2, CCL8 and CCL11 protein expression. In PsA L, chemokine mRNA correlated with protein expression, but protein expression of chemokine ligands did not correlate with ACKR2 expression.Conclusion:This data set shows expected upregulation of chemokines and their receptors in PsA L but relatively unchanged gene expression in PsA U, which contrasts to previous studies in psoriasis. Notably, this study demonstrates a strong upregulation of ACKR2 in keratinocytes in PsA L, with unchanged expression in PsA U. The RNA expression and preliminary protein data suggest that ACKR2 has little effect on the levels of its ligands in PsA skin lesions. However, this study may have missed local effects of ACKR2 in the epidermis.References:[1]Singh, M.D., et al.,Elevated expression of the chemokine-scavenging receptor D6 is associated with impaired lesion development in psoriasis.Am J Pathol, 2012.181(4): p. 1158-64.Acknowledgments:Funded by the Chief Scientist Office and a private donation to the University of Glasgow. Dr Sabarinadh Chilaka helped to prepare libraries for RNA sequencing.Disclosure of Interests:Hanna Johnsson: None declared, John Cole: None declared, Gillian Wilson: None declared, Marieke Pingen: None declared, Fiona McMonagle: None declared, Susan Holmes: None declared, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Gerard Graham: None declared
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Di Donato, Rachele, Raffaella Bonecchi, and Francesca Albano. "Canonical and atypical chemokine receptors in the neutrophil life cycle." Cytokine 169 (September 2023): 156297. http://dx.doi.org/10.1016/j.cyto.2023.156297.
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Russo, Remo C., Benedetta Savino, Massimiliano Mirolo, Chiara Buracchi, Giovanni Germano, Achille Anselmo, Luca Zammataro, et al. "The atypical chemokine receptor ACKR2 drives pulmonary fibrosis by tuning influx of CCR2+ and CCR5+ IFNγ-producing γδT cells in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 314, no. 6 (June 1, 2018): L1010—L1025. http://dx.doi.org/10.1152/ajplung.00233.2017.
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Chemokines coordinate lung inflammation and fibrosis by acting on chemokine receptors expressed on leukocytes and other cell types. Atypical chemokine receptors (ACKRs) bind, internalize, and degrade chemokines, tuning homeostasis and immune responses. ACKR2 recognizes and decreases the levels of inflammatory CC chemokines. The role of ACKR2 in fibrogenesis is unknown. The purpose of the study was to investigate the role of ACKR2 in the context of pulmonary fibrosis. The effects of ACKR2 expression and deficiency during inflammation and fibrosis were analyzed using a bleomycin-model of fibrosis, ACKR2-deficient mice, bone marrow chimeras, and antibody-mediated leukocyte depletion. ACKR2 was upregulated acutely in response to bleomycin and normalized over time. ACKR2−/− mice showed reduced lethality and lung fibrosis. Bone marrow chimeras showed that lethality and fibrosis depended on ACKR2 expression in pulmonary resident (nonhematopoietic) cells but not on leukocytes. ACKR2−/− mice exhibited decreased expression of tissue-remodeling genes, reduced leukocyte influx, pulmonary injury, and dysfunction. ACKR2−/− mice had early increased levels of CCL5, CCL12, CCL17, and IFNγ and an increased number of CCR2+ and CCR5+ IFNγ-producing γδT cells in the airways counterbalanced by low Th17-lymphocyte influx. There was reduced accumulation of IFNγ-producing γδT cells in CCR2−/− and CCR5−/− mice. Moreover, depletion of γδT cells worsened the clinical symptoms induced by bleomycin and reversed the phenotype of ACKR2−/− mice exposed to bleomycin. ACKR2 controls the CC chemokine expression that drives the influx of CCR2+ and CCR5+ IFNγ-producing γδT cells, tuning the Th17 response that mediated pulmonary fibrosis triggered by bleomycin instillation.
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Sinitski, Dzmitry, Christos Kontos, Christine Krammer, Yaw Asare, Aphrodite Kapurniotu, and Jürgen Bernhagen. "Macrophage Migration Inhibitory Factor (MIF)-Based Therapeutic Concepts in Atherosclerosis and Inflammation." Thrombosis and Haemostasis 119, no. 04 (February 4, 2019): 553–66. http://dx.doi.org/10.1055/s-0039-1677803.
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AbstractChemokines orchestrate leukocyte recruitment in atherosclerosis and their blockade is a promising anti-atherosclerotic strategy, but few chemokine-based approaches have advanced into clinical trials, in part owing to the complexity and redundancy of the chemokine network. Macrophage migration inhibitory factor (MIF) is a pivotal mediator of atherosclerotic lesion formation. It has been characterized as an inflammatory cytokine and atypical chemokine that promotes atherogenic leukocyte recruitment and lesional inflammation through interactions with the chemokine receptors CXCR2 and CXCR4, but also exhibits phase-specific CD74-mediated cardioprotective activity. The unique structural properties of MIF and its homologue MIF-2/D-DT offer intriguing therapeutic opportunities including small molecule-, antibody- and peptide-based approaches that may hold promise as inhibitors of atherosclerosis, while sparing tissue-protective classical chemokine pathways. In this review, we summarize the pros and cons of anti-MIF protein strategies and discuss their molecular characteristics and receptor specificities with a focus on cardiovascular disease.
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Cheng, Xiaoyun, and Mien-Chie Hung. "Regulation of Breast Cancer Metastasis by Atypical Chemokine Receptors: Fig. 1." Clinical Cancer Research 15, no. 9 (April 21, 2009): 2951–53. http://dx.doi.org/10.1158/1078-0432.ccr-09-0141.
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Degroot, Gaetan-Nagim, Valentin Lepage, Marc Parmentier, and Jean-Yves Springael. "The Atypical Chemerin Receptor GPR1 Displays Different Modes of Interaction with β-Arrestins in Humans and Mice with Important Consequences on Subcellular Localization and Trafficking." Cells 11, no. 6 (March 18, 2022): 1037. http://dx.doi.org/10.3390/cells11061037.
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Atypical chemokine receptors (ACKRs) have emerged as a subfamily of chemokine receptors regulating the local bioavailability of their ligands through scavenging, concentration, or transport. The biological roles of ACKRs in human physiology and diseases are often studied by using transgenic mouse models. However, it is unknown whether mouse and human ACKRs share the same properties. In this study, we compared the properties of the human and mouse atypical chemerin receptor GPR1 and showed that they behave differently regarding their interaction with β-arrestins. Human hGPR1 interacts with β-arrestins as a result of chemerin stimulation, whereas its mouse orthologue mGPR1 displays a strong constitutive interaction with β-arrestins in basal conditions. The constitutive interaction of mGPR1 with β-arrestins is accompanied by a redistribution of the receptor from the plasma membrane to early and recycling endosomes. In addition, β-arrestins appear mandatory for the chemerin-induced internalization of mGPR1, whereas they are dispensable for the trafficking of hGPR1. However, mGPR1 scavenges chemerin and activates MAP kinases ERK1/2 similarly to hGPR1. Finally, we showed that the constitutive interaction of mGPR1 with β-arrestins required different structural constituents, including the receptor C-terminus and arginine 3.50 in the second intracellular loop. Altogether, our results show that sequence variations within cytosolic regions of GPR1 orthologues influence their ability to interact with β-arrestins, with important consequences on GPR1 subcellular distribution and trafficking.
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Tan, Wee Yee, Boon Yin Khoo, and Ai Lan Chew. "Pichia-Expressed Recombinant D6 and DARC Negatively Affect Cell Migration and Invasion of Breast Cancer Cells." Sains Malaysiana 50, no. 10 (October 31, 2021): 3015–33. http://dx.doi.org/10.17576/jsm-2021-5010-15.
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Atypical chemokine receptor proteins are termed ‘decoy proteins’ as their binding to the respective ligands does not lead to a typical signaling pathway but intercepts the action of chemokines. This method of chemokine activity regulation may also function in tumor suppression. D6 and DARC (Duffy Antigen Receptor for Chemokines) have been reported as decoy chemokine receptors in cancer studies. Purified Pichia-expressed D6 and DARC, produced in-house, were used in cell-based studies to test their biological activities. Cell viability tests showed that recombinant D6 and DARC did not affect cell viability significantly, suggesting that they were not involved in breast cancer cell death. Wound healing assays showed that the presence of recombinant D6 or DARC at 10 µg/mL optimally inhibited the migration of breast cancer cells. ELISA showed an inverse relationship between the recombinant proteins and CCL2 levels in the treated cells. Migration assay using Boyden chamber demonstrated the function of the recombinant proteins in inhibiting chemotaxis activity of treated cells. Invasion assay showed the ability of the recombinant proteins in inhibiting the invasion property of treated cells. Comparison of single and combinatorial effects of the recombinant proteins showed that the combination of D6 and DARC at a 1:1 ratio (10 µg/mL) is most effective in reducing CCL2 levels and inhibiting the migration and invasion of treated cells. It was shown that the purified Pichia-expressed recombinant D6 and DARC are the negative regulators of breast cancer cell migration and invasion, and the inhibition effects were greater when they were used in combination.
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Pan, Li, Jianliang Lv, Zhongwang Zhang, and Yongguang Zhang. "Adaptation and Constraint in the Atypical Chemokine Receptor Family in Mammals." BioMed Research International 2018 (September 24, 2018): 1–9. http://dx.doi.org/10.1155/2018/9065181.
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Atypical chemokine receptors (ACKRs) are a subclass of G protein-coupled receptors characterized by promiscuity of ligand binding and an obvious inability to signal after ligand binding. Although some discoveries regarding this family in Homo sapiens and other species have been reported in some studies, the evolution and function of multiple ACKR in mammals have not yet been clearly understood. We performed an evolutionary analysis of ACKR genes (ACKR1, ACKR2, ACKR3, and ACKR4) in mammals. Ninety-two full-length ACKR genes from 27 mammal species were retrieved from the Genbank and Ensemble databases. Phylogenetic analysis showed that there were four well-conserved subfamilies in mammals. Synteny analysis revealed that ACKR genes formed conserved linkage groups with their adjacent genes across mammalian species, facilitating the identification of ACKRs in as yet unannotated genome datasets. Analysis of the site-specific profiles established by posterior probability revealed the positive-selection sites to be distributed mainly in the ligand binding region of ACKR1. This study highlights the molecular evolution of the ACKR gene family in mammals and identifies the critical amino acid residues likely to be relevant to ligand binding. Further experimental verification of these findings may provide valuable information regarding the ACKR’s biochemical and physiological functions.
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Burger, Nathalie, Andrea Haerzschel, Marion Leick, Tanja Nicole Hartmann, Julie Catusse, and Meike Burger. "CCL19 Induced Responses Are Differentially Regulated by Atypical Chemokine Receptor CRAM and Its Classical Chemokine Receptor CCR7 in B-CLL Cells." Blood 118, no. 21 (November 18, 2011): 4896. http://dx.doi.org/10.1182/blood.v118.21.4896.4896.
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Abstract Abstract 4896 Introduction: Chemokines are known to play an important role in the migration and survival of B-CLL cells. The non-signalling chemokine receptors, including DARC, D6 and CCX-CKR, have recently been shown to be involved in chemokine clearance and activity regulation. The human chemokine receptor CRAM is the most recently identified member of this atypical group. CRAM is expressed on B cells in a maturation-stage dependent manner, and to variable degrees on B-CLL cells. We have recently shown that it competitively binds CCL19 and that this binding is not followed by classical chemokine responses. CCL19 and its signalling receptor CCR7 are centrally involved in B cell localisation and maturation within the secondary lymphoid tissues. CCR7 is also highly expressed on B cells from CLL patients and mediates migration towards its ligands CCL19 and CCL21 which have been shown to be present at higher concentrations in serum of patients with lymphadenopathia compared to patients without. In this study we investigate the influence of CRAM on the CCL19 dependent responses of B-CLL cells and potential correlations to clinical data with a specific focus on lymphadenopathia. Results: We demonstrate that B cells from patients with B-CLL present high, but variable degrees of CCR7 and CRAM expression. Patients with compared to patients without lymphadenopathia show a higher CRAM expression level whereas the CCR7 expression is not significantly different. In single samples showing extremly high CRAM expression the migration towards CCL19 is reduced compared to patients with lower CRAM expression. These observations confirm results in the B-CLL cell line MEC-1 showing increased migration toward CCL19 when CRAM expression is reduced using CRAM-siRNA. On the other hand, CRAM seems to be a chemokine presenter as we can show that it does not degrade its chemokine ligand but presents it on the surface of polarised cell layers. Thus, we assume that CRAM plays a role for cell migration, possibly transmigration and cell localisation within lymph nodes of B-CLL cells. Conclusions: We show that CRAM can act as an integrator of different recruitment and activation factors. It is associated to CCR7 driven recruitment of B cells by regulating CCL19 availability. Expression of CRAM differs in B cell malignancies for which CCL19 and CCL21 have already been shown to be implicated in lymphadenopathia. We therefore suggest that CRAM is an additional player in the localisation and differentiation/maturation processes of malignant B cells of B-CLL patients. Disclosures: No relevant conflicts of interest to declare.
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Ford, Laura B., Vuk Cerovic, Simon W. F. Milling, Gerard J. Graham, Chris A. H. Hansell, and Robert J. B. Nibbs. "Characterization of Conventional and Atypical Receptors for the Chemokine CCL2 on Mouse Leukocytes." Journal of Immunology 193, no. 1 (June 2, 2014): 400–411. http://dx.doi.org/10.4049/jimmunol.1303236.
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Calvello, Rosa, Chiara Porro, Dario Domenico Lofrumento, Melania Ruggiero, Maria Antonietta Panaro, and Antonia Cianciulli. "Decoy Receptors Regulation by Resveratrol in Lipopolysaccharide-Activated Microglia." Cells 12, no. 5 (February 21, 2023): 681. http://dx.doi.org/10.3390/cells12050681.
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Resveratrol is a polyphenol that acts as antioxidants do, protecting the body against diseases, such as diabetes, cancer, heart disease, and neurodegenerative disorders, such as Alzheimer’s (AD) and Parkinson’s diseases (PD). In the present study, we report that the treatment of activated microglia with resveratrol after prolonged exposure to lipopolysaccharide is not only able to modulate pro-inflammatory responses, but it also up-regulates the expression of decoy receptors, IL-1R2 and ACKR2 (atypical chemokine receptors), also known as negative regulatory receptors, which are able to reduce the functional responses promoting the resolution of inflammation. This result might constitute a hitherto unknown anti-inflammatory mechanism exerted by resveratrol on activated microglia.
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Kleist, Andrew B., Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie I. Anderson, et al. "Conformational selection guides β-arrestin recruitment at a biased G protein–coupled receptor." Science 377, no. 6602 (July 8, 2022): 222–28. http://dx.doi.org/10.1126/science.abj4922.
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G protein–coupled receptors (GPCRs) recruit β-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage β-arrestins but not G proteins, making them a model system for investigating the structural basis of β-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13 CH 3 -ε–methionine–labeled ACKR3, revealing that β-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular β-arrestin–coupling region. NMR studies of ACKR3 mutants defective in β-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides β-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.
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Dobroch, Jakub, Klaudia Bojczuk, Adrian Kołakowski, Marta Baczewska, and Paweł Knapp. "The Exploration of Chemokines Importance in the Pathogenesis and Development of Endometrial Cancer." Molecules 27, no. 7 (March 22, 2022): 2041. http://dx.doi.org/10.3390/molecules27072041.
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Endometrial cancer (EC) is one of the most frequent female malignancies. Because of a characteristic symptom, vaginal bleeding, EC is often diagnosed in an early stage. Despite that, some EC cases present an atypical course with rapid progression and poor prognosis. There have been multiple studies conducted on molecular profiling of EC in order to improve diagnostics and introduce personalized treatment. Chemokines—a protein family that contributes to inflammatory processes that may promote carcinogenesis—constitute an area of interest. Some chemokines and their receptors present alterations in expression in tumor microenvironment. CXCL12, which binds the receptors CXCR4 and CXCR7, is known for its impact on neoplastic cell proliferation, neovascularization and promotion of epidermal–mesenchymal transition. The CCL2–CCR2 axis additionally plays a pivotal role in EC with mutations in the LKB1 gene and activates tumor-associated macrophages. CCL20 and CCR6 are influenced by the RANK/RANKL pathway and alter the function of lymphocytes and dendritic cells. Another axis, CXCL10–CXCR3, affects the function of NK-cells and, interestingly, presents different roles in various types of tumors. This review article consists of analysis of studies that included the roles of the aforementioned chemokines in EC pathogenesis. Alterations in chemokine expression are described, and possible applications of drugs targeting chemokines are reviewed.
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del Molino del Barrio, Irene, Georgina Wilkins, Annette Meeson, Simi Ali, and John Kirby. "Breast Cancer: An Examination of the Potential of ACKR3 to Modify the Response of CXCR4 to CXCL12." International Journal of Molecular Sciences 19, no. 11 (November 14, 2018): 3592. http://dx.doi.org/10.3390/ijms19113592.
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Upon binding with the chemokine CXCL12, the chemokine receptor CXCR4 has been shown to promote breast cancer progression. This process, however, can be affected by the expression of the atypical chemokine receptor ACKR3. Given ACKR3’s ability to form heterodimers with CXCR4, we investigated how dual expression of both receptors differed from their lone expression in terms of their signalling pathways. We created single and double CXCR4 and/or ACKR3 Chinese hamster ovary (CHO) cell transfectants. ERK and Akt phosphorylation after CXCL12 stimulation was assessed and correlated with receptor internalization. Functional consequences in cell migration and proliferation were determined through wound healing assays and calcium flux. Initial experiments showed that CXCR4 and ACKR3 were upregulated in primary breast cancer and that CXCR4 and ACKR3 could form heterodimers in transfected CHO cells. This co-expression modified CXCR4’s Akt activation after CXCL12’s stimulation but not ERK phosphorylation (p < 0.05). To assess this signalling disparity, receptor internalization was assessed and it was observed that ACKR3 was recycled to the surface whilst CXCR4 was degraded (p < 0.01), a process that could be partially inhibited with a proteasome inhibitor (p < 0.01). Internalization was also assessed with the ACKR3 agonist VUF11207, which caused both CXCR4 and ACKR3 to be degraded after internalization (p < 0.05 and p < 0.001), highlighting its potential as a dual targeting drug. Interestingly, we observed that CXCR4 but not ACKR3, activated calcium flux after CXCL12 stimulation (p < 0.05) and its co-expression could increase cellular migration (p < 0.01). These findings suggest that both receptors can signal through ERK and Akt pathways but co-expression can alter their kinetics and internalization pathways.
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Bachelerie, Francoise, Adit Ben-Baruch, Amanda M. Burkhardt, Christophe Combadiere, Joshua M. Farber, Gerard J. Graham, Richard Horuk, et al. "International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors." Pharmacological Reviews 66, no. 1 (November 11, 2013): 1–79. http://dx.doi.org/10.1124/pr.113.007724.
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Korbecki, Jan, Mateusz Bosiacki, Piotr Stasiak, Emilian Snarski, Agnieszka Brodowska, Dariusz Chlubek, and Irena Baranowska-Bosiacka. "Clinical Aspects and Significance of β-Chemokines, γ-Chemokines, and δ-Chemokines in Molecular Cancer Processes in Acute Myeloid Leukemia (AML) and Myelodysplastic Neoplasms (MDS)." Cancers 16, no. 19 (September 24, 2024): 3246. http://dx.doi.org/10.3390/cancers16193246.
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Background/Objectives: Acute myeloid leukemia (AML) is a type of leukemia with a very poor prognosis. Consequently, this neoplasm is extensively researched to discover new therapeutic strategies. One area of investigation is the study of intracellular communication and the impact of the bone marrow microenvironment on AML cells, with chemokines being a key focus. The roles of β-chemokines, γ-chemokines, and δ-chemokines in AML processes have not yet been sufficiently characterized. Methods: This publication summarizes all available knowledge about these chemotactic cytokines in AML and myelodysplastic neoplasm (MDS) processes and presents potential therapeutic strategies to combat the disease. The significance of β-chemokines, γ-chemokines, and δ-chemokines is detailed, including CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES), CCL23, CCL28, and CX3CL1 (fractalkine). Additionally, the importance of atypical chemokine receptors in AML is discussed, specifically ACKR1, ACKR2, ACKR4, and CCRL2. Results/Conclusions: The focus is on the effects of these chemokines on AML cells, particularly their influence on proliferation and resistance to anti-leukemic drugs. Intercellular interactions with non-AML cells, such as mesenchymal stem cells (MSC), macrophages, and regulatory T cells (Treg), are also characterized. The clinical aspects of chemokines are thoroughly explained, including their effect on overall survival and the relationship between their blood levels and AML characteristics.