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Journal articles on the topic 'Chemokine'
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1
Schwartzkopff, Franziska, Frank Petersen, Tobias Alexander Grimm, and Ernst Brandt. "CXC chemokine ligand 4 (CXCL4) down-regulates CC chemokine receptor expression on human monocytes." Innate Immunity 18, no. 1 (November 18, 2010): 124–39. http://dx.doi.org/10.1177/1753425910388833.
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During acute inflammation, monocytes are essential in abolishing invading micro-organisms and encouraging wound healing. Recruitment by CC chemokines is an important step in targeting monocytes to the inflamed tissue. However, cell surface expression of the corresponding chemokine receptors is subject to regulation by various endogenous stimuli which so far have not been comprehensively identified. We report that the platelet-derived CXC chemokine ligand 4 (CXCL4), a known activator of human monocytes, induces down-regulation of CC chemokine receptors (CCR) 1, −2, and −5, resulting in drastic impairment of monocyte chemotactic migration towards cognate CC chemokine ligands (CCL) for these receptors. Interestingly, CXCL4-mediated down-regulation of CCR1, CCR2 and CCR5 was strongly dependent on the chemokine’s ability to stimulate autocrine/paracrine release of TNF-α. In turn, TNF-α induced the secretion CCL3 and CCL4, two chemokines selective for CCR1 and CCR5, while the secretion of CCR2-ligand CCL2 was TNF-α-independent. Culture supernatants of CXCL4-stimulated monocytes as well as chemokine-enriched preparations thereof reproduced CXCL4-induced CCR down-regulation. In conclusion, CXCL4 may act as a selective regulator of monocyte migration by stimulating the release of autocrine, receptor-desensitizing chemokine ligands. Our results stress a co-ordinating role for CXCL4 in the cross-talk between platelets and monocytes during early inflammation.
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Palacios-Arreola, M. Isabel, Karen E. Nava-Castro, Julieta I. Castro, Eduardo García-Zepeda, Julio C. Carrero, and Jorge Morales-Montor. "The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets." Journal of Immunology Research 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/849720.
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Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system.
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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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Romero, Joan Miguel, Emma Titmuss, Yifan Wang, James Vafiadis, Alain Pacis, Gun Ho Jang, Amy Zhang, et al. "Assessment of a 4-chemokine signature in prediction of T-cell inflammation and response to immune checkpoint inhibition across tumor types." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2558. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2558.
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2558 Background: Immune checkpoint inhibitors (ICI) are highly effective in select cancers. Novel predictors of T cell-inflammation may identify a broader subset of tumors with ICI responsiveness. Our group has identified four chemokines (CCL4, CCL5, CXCL9, CXLC10) able to predict a T cell-inflamed phenotype in primary and metastatic pancreatic tumors. Here, we test whether this 4-chemokine signature can predict T cell-inflammation across additional tumor types and response to ICI. Methods: Using matched genomic and transcriptomic data from 6,455 patients spanning 25 tumor types from The Cancer Genome Atlas, we searched for associations between the 4-chemokine signature and metrics of antitumor immunity. Further, we tested the association of this signature with markers of DNA damage repair deficiency. We also investigated the ability of this signature to predict response to immunotherapy using real-world data from a pan-cancer cohort of 82 patients in the Personalized OncoGenomics Program who had received ICI. Results: The majority of tumor types displayed sub-populations with high expression of the 4-chemokines (4-chemokinehi) and transcriptional hallmarks of the cancer-immunity cycle. Testicular germ cell tumors, cervical squamous cell carcinomas, and head and neck squamous cell carcinomas were the strongest expressors of the signature. Immunomodulatory genes, including PD-L1, PD-1, TIM3, LAG3, TIGIT, CTLA-4, and FASLG, were significantly overexpressed (p<0.05) in the 4-chemokinehi cohorts. Genesets of processes involved in the cancer-immunity cycle, including MHC I expression and cytolytic activity, were upregulated in the 4-chemokinehi cohorts (p<0.05). While a global relationship between tumor mutation burden (TMB) and 4-chemokine expression across tumor histological type was seen (rho=0.42, p=0.02), high TMB was associated with only a subset of 4-chemokinehi tumors. Among patients treated with ICIs, those with 4-chemokinehi tumors had a longer median time to progression (104 versus 71 days, p=0.013) and overall survival (391 versus 195 days, p=0.016). The 4-chemokine signature outperformed TMB for overall survival prediction. Conclusions: Sub-populations of T cell-inflamed patients exist across tumor types and may therefore respond favourably to ICI. The 4-chemokine signature has the potential to select a wider spectrum of patients that may benefit from ICIs. [Table: see text]
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Ji, Guang. "Advances in Research on the Role of Chemokines in Occurrence and Development of Autoimmune Thyroid Disease." Infection International 4, no. 3 (September 1, 2015): 59–63. http://dx.doi.org/10.1515/ii-2017-0108.
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AbstractChemokines can be divided into four categories: α, β, γ, and δ. Chemokine α is related to neutrophil chemotaxis. Chemokine β is correlated with adsorption of monocytes, basophils, and eosinophils. Chemokine γ is mainly a lymphocyte chemokine. Function of chemokine δ remains unclear. Chemokines α and β are primarily related to occurrence and development of autoimmune thyroid disease. This study reviews chemokines and their receptors that are related to Graves’ disease and Hashimoto’s thyroiditis.
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Zhang, Peng-Fei, Chuang Wang, Le Zhang, and Qiu Li. "Reversing chemokine/chemokine receptor mismatch to enhance the antitumor efficacy of CAR-T cells." Immunotherapy 14, no. 6 (April 2022): 459–73. http://dx.doi.org/10.2217/imt-2021-0228.
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Currently, the antitumor efficacy of chimeric antigen receptor T cells in solid tumors is modest. Both chemokines and their receptors play a key role in the proliferation of cancer cells, tumor angiogenesis, organ-selective metastasis and migration of immune cells to solid tumors. Unfortunately, frequent chemokine/chemokine receptor ‘mismatch’ between effector cells and the tumor microenvironment results in inefficient T-cell infiltration and antitumor efficacy. Thus, reversing the ‘mismatch’ of chemokines and chemokine receptors appears to be a promising method for promoting T-cell infiltration into the tumor and enhancing their antitumor efficacy. In this review, we discuss functions of the chemokine/chemokine receptor axis in cancer immunity and the current understanding, challenges and prospects for improving the effect of chimeric antigen receptor T cells by reversing the mismatch between chemokines and chemokine receptors.
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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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Groves, D. T., and Y. Jiang. "Chemokines, a Family of Chemotactic Cytokines." Critical Reviews in Oral Biology & Medicine 6, no. 2 (April 1995): 109–18. http://dx.doi.org/10.1177/10454411950060020101.
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Chemokines are low-molecular-weight proteins that stimulate recruitment of leukocytes. They are secondary proinflammatory mediators that are induced by primary pro-inflammatory mediators such as interleukin-I (IL-1) or tumor necrosis factor (TNF). The physiologic importance of this family of mediators is derived from their specificity. Unlike the classic leukocyte chemo-attractants, which have little specificity, members of the chemokine family induce recruitment of well-defined leukocyte subsets. Thus, chemokine expression can account for the presence of different types of leukocytes observed in various normal or pathologic states. There are two major chemokine sub-families based upon the position of cysteine residues, i . e.,CXC and CC. All members of the CXC chemokine sub-family have an intervening amino acid between the first two cysteines; members of the CC chemokine sub-family have two adjacent cysteines. As a general rule (with some notable exceptions), members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and a small sub-set of lymphocytes. This review discusses the potential role of chemokines in inflammation and focuses on the two best-characterized chemokines, monocyte chemoattractant protein-1 (MCP-1 a CC chemokine, and interleukin-8 (IL-8), a member of the CXC chemokine sub-family.
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Luesink, Maaike, Jeroen L. A. Pennings, Willemijn M. Wissink, Peter C. M. Linssen, Petra Muus, Rolph Pfundt, Theo J. M. de Witte, Bert A. van der Reijden, and Joop H. Jansen. "Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome." Blood 114, no. 27 (December 24, 2009): 5512–21. http://dx.doi.org/10.1182/blood-2009-02-204834.
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Abstract In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.
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Parry, Christopher M., J. Pedro Simas, Vincent P. Smith, C. Andrew Stewart, Anthony C. Minson, Stacey Efstathiou, and Antonio Alcami. "A Broad Spectrum Secreted Chemokine Binding Protein Encoded by a Herpesvirus." Journal of Experimental Medicine 191, no. 3 (February 7, 2000): 573–78. http://dx.doi.org/10.1084/jem.191.3.573.
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Chemokines are a family of small proteins that interact with seven-transmembrane domain receptors and modulate the migration of immune cells into sites of inflammation and infection. The murine gammaherpesvirus 68 M3 gene encodes a secreted 44-kD protein with no sequence similarity to known chemokine receptors. We show that M3 binds a broad range of chemokines, including CC, CXC, C, and CX3C chemokines, but does not bind human B cell–specific nor mouse neutrophil–specific CXC chemokines. This herpesvirus chemokine binding protein (hvCKBP) blocks the interaction of chemokines with high-affinity cellular receptors and inhibits chemokine-induced elevation of intracellular calcium levels. hvCKBP is the first soluble chemokine receptor identified in herpesviruses; it represents a novel protein structure with the ability to bind all subfamilies of chemokines in solution and has potential therapeutic applications.
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Alcamí, Antonio, Julian A. Symons, Paul D. Collins, Timothy J. Williams, and Geoffrey L. Smith. "Blockade of Chemokine Activity by a Soluble Chemokine Binding Protein from Vaccinia Virus." Journal of Immunology 160, no. 2 (January 15, 1998): 624–33. http://dx.doi.org/10.4049/jimmunol.160.2.624.
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Abstract Chemokines direct migration of immune cells into sites of inflammation and infection. Chemokine receptors are seven-transmembrane domain proteins that, in contrast to other cytokine receptors, cannot be easily engineered as soluble chemokine inhibitors. Poxviruses encode several soluble cytokine receptors to evade immune surveillance, providing new strategies for immune modulation. Here we show that vaccinia virus and other orthopoxviruses (cowpox and camelpox) express a secreted 35-kDa chemokine binding protein (vCKBP) with no sequence similarity to known cellular chemokine receptors. The vCKBP binds CC, but not CXC or C, chemokines with high affinity (Kd = 0.1–15 nM for different CC chemokines), blocks the interaction of chemokines with cellular receptors, and inhibits chemokine-induced elevation of intracellular calcium levels and cell migration in vitro, thus representing a soluble inhibitor that binds and sequesters chemokines. The potential of vCKBP as a therapeutic agent in vivo was illustrated in a guinea pig skin model by the blockade of eotaxin-induced eosinophil infiltration, a feature of allergic inflammatory reactions. Furthermore, vCKBP may enable the rational design of antagonists to neutralize pathogens that use chemokine receptors to initiate infection, such as HIV or the malarial parasite.
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van Berkel, Victor, John Barrett, H. Lee Tiffany, Daved H. Fremont, Philip M. Murphy, Grant McFadden, Samuel H. Speck, and Herbert W. Virgin. "Identification of a Gammaherpesvirus Selective Chemokine Binding Protein That Inhibits Chemokine Action." Journal of Virology 74, no. 15 (August 1, 2000): 6741–47. http://dx.doi.org/10.1128/jvi.74.15.6741-6747.2000.
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ABSTRACT Chemokines are involved in recruitment and activation of hematopoietic cells at sites of infection and inflammation. The M3 gene of γHV68, a gamma-2 herpesvirus that infects and establishes a lifelong latent infection and chronic vasculitis in mice, encodes an abundant secreted protein during productive infection. The M3 gene is located in a region of the genome that is transcribed during latency. We report here that the M3 protein is a high-affinity broad-spectrum chemokine scavenger. The M3 protein bound the CC chemokines human regulated upon activation of normal T-cell expressed and secreted (RANTES), murine macrophage inflammatory protein 1α (MIP-1α), and murine monocyte chemoattractant protein 1 (MCP-1), as well as the human CXC chemokine interleukin-8, the murine C chemokine lymphotactin, and the murine CX3C chemokine fractalkine with high affinity (Kd = 1.6 to 18.7 nM). M3 protein chemokine binding was selective, since the protein did not bind seven other CXC chemokines (Kd > 1 μM). Furthermore, the M3 protein abolished calcium signaling in response to murine MIP-1α and murine MCP-1 and not to murine KC or human stromal cell-derived factor 1 (SDF-1), consistent with the binding data. The M3 protein was also capable of blocking the function of human CC and CXC chemokines, indicating the potential for therapeutic applications. Since the M3 protein lacks homology to known chemokines, chemokine receptors, or chemokine binding proteins, these studies suggest a novel herpesvirus mechanism of immune evasion.
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Mackay, Charles R. "Chemokines: What chemokine is that?" Current Biology 7, no. 6 (June 1997): R384—R386. http://dx.doi.org/10.1016/s0960-9822(06)00181-3.
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ABBADIE, C. "Chemokines, chemokine receptors and pain." Trends in Immunology 26, no. 10 (October 2005): 529–34. http://dx.doi.org/10.1016/j.it.2005.08.001.
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Kaplan, Allen P. "Chemokines, Chemokine Receptors and Allergy." International Archives of Allergy and Immunology 124, no. 4 (2001): 423–31. http://dx.doi.org/10.1159/000053777.
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Youn, Byung-S., Charlie Mantel, and Hal E. Broxmeyer1. "Chemokines, chemokine receptors and hematopoiesis." Immunological Reviews 177, no. 1 (October 2000): 150–74. http://dx.doi.org/10.1034/j.1600-065x.2000.17701.x.
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Paoletti, Samantha, Vibor Petkovic, Silvia Sebastiani, M. Gabriela Danelon, Mariagrazia Uguccioni, and Basil O. Gerber. "A rich chemokine environment strongly enhances leukocyte migration and activities." Blood 105, no. 9 (May 1, 2005): 3405–12. http://dx.doi.org/10.1182/blood-2004-04-1648.
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AbstractThe migration of leukocytes in immune surveillance and inflammation is largely determined by their response to chemokines. While the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how leukocytes integrate the messages provided by different chemokines that are concomitantly produced in physiologic or pathologic situations in vivo. We present evidence for a novel regulatory mechanism of leukocyte trafficking. Our data are consistent with a mode of action where CC-chemokine receptor 7 (CCR7) agonists and unrelated, nonagonist chemokines first form a heteromeric complex, in the presence of which the triggering of CCR7 can occur at a much lower agonist concentration. The increase is synergistic and can be evoked by many but not all chemokines. Chemokine-induced synergism might provide an amplification system in “chemokine-rich” tissues, rendering leukocytes more competent to respond to migratory cues.
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De Zutter, Alexandra, Jo Van Damme, and Sofie Struyf. "The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer." Cancers 13, no. 17 (August 24, 2021): 4247. http://dx.doi.org/10.3390/cancers13174247.
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Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity is the NH2-terminal truncation by peptidases. CD26 is a dipeptidyl peptidase (DPPIV), which typically clips a NH2-terminal dipeptide from the chemokine. With a certain degree of selectivity in terms of chemokine substrate, CD26 only recognizes chemokines with a penultimate proline or alanine. Chemokines can be protected against CD26 recognition by specific amino acid residues within the chemokine structure, by oligomerization or by binding to cellular glycosaminoglycans (GAGs). Upon truncation, the binding affinity for receptors and GAGs is altered, which influences chemokine function. The consequences of CD26-mediated clipping vary, as unchanged, enhanced, and reduced activities are reported. In tumors, CD26 most likely has the most profound effect on CXCL12 and the interferon (IFN)-inducible CXCR3 ligands, which are converted into receptor antagonists upon truncation. Depending on the tumor type, expression of CD26 is upregulated or downregulated and often results in the preferential generation of the chemokine isoform most favorable for tumor progression. Considering the tight relationship between chemokine sequence and chemokine binding specificity, molecules with the appropriate characteristics can be chemically engineered to provide innovative therapeutic strategies in a cancer setting.
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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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Dyer, Douglas P., Elisa Migliorini, Catherina L. Salanga, Dhruv Thakar, Tracy M. Handel, and Ralf P. Richter. "Differential structural remodelling of heparan sulfate by chemokines: the role of chemokine oligomerization." Open Biology 7, no. 1 (January 2017): 160286. http://dx.doi.org/10.1098/rsob.160286.
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Chemokines control the migration of cells in normal physiological processes and in the context of disease such as inflammation, autoimmunity and cancer. Two major interactions are involved: (i) binding of chemokines to chemokine receptors, which activates the cellular machinery required for movement; and (ii) binding of chemokines to glycosaminoglycans (GAGs), which facilitates the organization of chemokines into haptotactic gradients that direct cell movement. Chemokines can bind and activate their receptors as monomers; however, the ability to oligomerize is critical for the function of many chemokines in vivo . Chemokine oligomerization is thought to enhance their affinity for GAGs, and here we show that it significantly affects the ability of chemokines to accumulate on and be retained by heparan sulfate (HS). We also demonstrate that several chemokines differentially rigidify and cross-link HS, thereby affecting HS rigidity and mobility, and that HS cross-linking is significantly enhanced by chemokine oligomerization. These findings suggest that chemokine–GAG interactions may play more diverse biological roles than the traditional paradigms of physical immobilization and establishment of chemokine gradients; we hypothesize that they may promote receptor-independent events such as physical re-organization of the endothelial glycocalyx and extracellular matrix, as well as signalling through proteoglycans to facilitate leukocyte adhesion and transmigration.
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Weber, Michele, Emma Blair, Clare V. Simpson, Maureen O'Hara, Paul E. Blackburn, Antal Rot, Gerard J. Graham, and Robert J. B. Nibbs. "The Chemokine Receptor D6 Constitutively Traffics to and from the Cell Surface to Internalize and Degrade Chemokines." Molecular Biology of the Cell 15, no. 5 (May 2004): 2492–508. http://dx.doi.org/10.1091/mbc.e03-09-0634.
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The D6 heptahelical membrane protein, expressed by lymphatic endothelial cells, is able to bind with high affinity to multiple proinflammatory CC chemokines. However, this binding does not allow D6 to couple to the signaling pathways activated by typical chemokine receptors such as CC-chemokine receptor-5 (CCR5). Here, we show that D6, like CCR5, can rapidly internalize chemokines. However, D6-internalized chemokines are more effectively retained intracellularly because they more readily dissociate from the receptor during vesicle acidification. These chemokines are then degraded while the receptor recycles to the cell surface. Interestingly, D6-mediated chemokine internalization occurs without bringing about a reduction in cell surface D6 levels. This is possible because unlike CCR5, D6 is predominantly localized in recycling endosomes capable of trafficking to and from the cell surface in the absence of ligand. When chemokine is present, it can enter the cells associated with D6 already destined for internalization. By this mechanism, D6 can target chemokines for degradation without the necessity for cell signaling, and without desensitizing the cell to subsequent chemokine exposure.
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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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Alluri, Santosh R., Yusuke Higashi, and Kun-Eek Kil. "PET Imaging Radiotracers of Chemokine Receptors." Molecules 26, no. 17 (August 26, 2021): 5174. http://dx.doi.org/10.3390/molecules26175174.
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Chemokines and chemokine receptors have been recognized as critical signal components that maintain the physiological functions of various cells, particularly the immune cells. The signals of chemokines/chemokine receptors guide various leukocytes to respond to inflammatory reactions and infectious agents. Many chemokine receptors play supportive roles in the differentiation, proliferation, angiogenesis, and metastasis of diverse tumor cells. In addition, the signaling functions of a few chemokine receptors are associated with cardiac, pulmonary, and brain disorders. Over the years, numerous promising molecules ranging from small molecules to short peptides and antibodies have been developed to study the role of chemokine receptors in healthy states and diseased states. These drug-like candidates are in turn exploited as radiolabeled probes for the imaging of chemokine receptors using noninvasive in vivo imaging, such as positron emission tomography (PET). Recent advances in the development of radiotracers for various chemokine receptors, particularly of CXCR4, CCR2, and CCR5, shed new light on chemokine-related cancer and cardiovascular research and the subsequent drug development. Here, we present the recent progress in PET radiotracer development for imaging of various chemokine receptors.
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Do, Ha Thi Thu, Chang Hoon Lee, and Jungsook Cho. "Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers." Cancers 12, no. 2 (January 24, 2020): 287. http://dx.doi.org/10.3390/cancers12020287.
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Chemokines are chemotactic cytokines that mediate immune cell chemotaxis and lymphoid tissue development. Recent advances have indicated that chemokines and their cognate receptors play critical roles in cancer-related inflammation and cancer progression. On the basis of these findings, the chemokine system has become a new potential drug target for cancer immunotherapy. In this review, we summarize the essential roles of the complex network of chemokines and their receptors in cancer progression. Furthermore, we discuss the potential value of the chemokine system as a cancer prognostic marker. The chemokine system regulates the infiltration of immune cells into the tumor microenvironment, which induces both pro- and anti-immunity and promotes or suppresses tumor growth and proliferation, angiogenesis, and metastasis. Increasing evidence indicates the promising prognostic value of the chemokine system in cancer patients. While CCL2, CXCL10, and CX3CL1/CX3CR1 can serve as favorable or unfavorable prognostic factors depending on the cancer types, CCL14 and XCL1 possess good prognostic value. Other chemokines such as CXCL1, CXCL8, and CXCL12 are poor prognostic markers. Despite vast advances in our understanding of the complex nature of the chemokine system in tumor biology, knowledge about the multifaceted roles of the chemokine system in different types of cancers is still limited. Further studies are necessary to decipher distinct roles within the chemokine system in terms of cancer progression and to validate their potential value in cancer prognosis.
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Colditz, Ian, Martin Schneider, Monika Pruenster, and Antal Rot. "Chemokines at large: In-vivo mechanisms of their transport, presentation and clearance." Thrombosis and Haemostasis 97, no. 05 (2007): 688–93. http://dx.doi.org/10.1160/th07-02-0105.
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SummaryCompelling evidence implicates chemokines in the induction of leukocyte emigration from blood into tissues.This arguably most fundamental effect of chemokines is accomplished by triggering cognate classical G-protein-coupled chemokine receptors on the leukocyte surface. In vitro, these same receptors mediate leukocyte migration; however, the mechanisms of chemokine-induced migration differ between in-vivo and in-vitro settings. Leukocyte egress from blood is greatly influenced by haemodynamic conditions and requires full cooperation of endothelial cells.The behaviour of chemokines in their“native habitat” in vivo is controlled by their interaction with several accessory molecules which influence immobilisation, transport, clearance and degradation of chemokines and thereby determine the sites and duration of their action. Here we discuss peculiarities of the invivo actions of chemokines,the mechanisms of chemokine interaction with receptors and auxiliary molecules including interceptors, glycosaminoglycans and enzymes and illustrate how these interactions influence the outcome of chemokine activities in vivo.
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Tadagaki, Kenjiro, Kazushi Nakano, and Koichi Yamanishi. "Human Herpesvirus 7 Open Reading Frames U12 and U51 Encode Functional β-Chemokine Receptors." Journal of Virology 79, no. 11 (June 1, 2005): 7068–76. http://dx.doi.org/10.1128/jvi.79.11.7068-7076.2005.
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ABSTRACT Human herpesvirus 7 (HHV-7), which belongs to the betaherpesvirus subfamily and infects mainly CD4+ T cells in vitro, infects children during infancy. HHV-7 contains two genes, U12 and U51, that encode putative homologs of cellular G-protein-coupled receptors. To analyze the biological function of the U12 and U51 genes, we cloned these genes and expressed the proteins in cells. U12 and U51 encoded functional calcium-mobilizing receptors for β-chemokines, which include thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), EBI1-ligand chemokine (ELC), and secondary lymphoid-tissue chemokine (SLC), but not for other chemokines, suggesting that the chemokine selectivities of the U12 and U51 products were distinct from those of the known mammalian chemokine receptors. ELC and SLC induced migration in Jurkat cells stably expressing U12, but TARC and MDC did not. In contrast, none of these chemokines induced migration in Jurkat cells stably expressing U51. Together, these data indicate that the products of U12 and U51 may play important and different roles in the pathogenesis of HHV-7 through transmembrane signaling.
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BANAS, BERNHARD, BRUNO LUCKOW, MARCUS MÖLLER, CHRISTIANE KLIER, PETER J. NELSON, ERIK SCHADDE, MANFRED BRIGL, et al. "Chemokine and Chemokine Receptor Expression in a Novel Human Mesangial Cell Line." Journal of the American Society of Nephrology 10, no. 11 (November 1999): 2314–22. http://dx.doi.org/10.1681/asn.v10112314.
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Abstract. Chemokines are thought to play a pivotal role in mediating the selective migration of leukocytes into sites of tissue injury. The local production of chemokines by mesangial cells (MC) has been linked to inflammatory processes within the glomerulus. To study the chemokine biology of human MC, an immortalized human MC line was generated and then chemokine and chemokine receptor expression was examined in response to various proinflammatory stimuli. The results show that human MC have a specific and limited repertoire of chemokine expression. The stimulus-specific regulation of the chemokines monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), interleukin-8 (IL-8), and IP-10 was demonstrated using RNase protection assays. Transcripts for the chemokines MIP-1α, MIP-1β, I-309, or lymphotactin could not be detected. The expression of CC chemokine receptors was investigated by reverse transcription-PCR and RNase protection assays. MC stimulated with interferon-γ (IFN-γ) expressed mRNA for the chemokine receptor CCR1. The expression could be further increased by activating the cells with a combination of tumor necrosis factor-α (TNF-α), IL-1β, and IFN-γ. Under these conditions, no mRNA for CCR2, CCR3, CCR4, CCR5, or CCR8 was detected. A comparison of the immortalized human mesangial cells with primary cells showed identical expression patterns of chemokine receptors. To demonstrate functional activity of chemokine receptors expressed by human MC, chemotaxis assays were performed. MC stimulated with a combination of TNF-α, IL-1β, and IFN-γ, but not unstimulated MC, migrated toward a RANTES gradient. Eotaxin did not enhance the migratory activity of human MC. In summary, a novel human mesangial cell line was established and the pattern of chemokine expression was examined. For the first time, the inducible expression of functionally active CCR1 by human MC was shown.
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Struyf, Sofie, Paul Proost, Jean-Pierre Lenaerts, Griet Stoops, Anja Wuyts, and Jo Van Damme. "Identification of a blood-derived chemoattractant for neutrophils and lymphocytes as a novel CC chemokine, Regakine-1." Blood 97, no. 8 (April 15, 2001): 2197–204. http://dx.doi.org/10.1182/blood.v97.8.2197.
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Abstract Chemokines constitute a large family of chemotactic cytokines that selectively attract different blood cell types. Although most inflammatory chemoattractants are only induced and released in the circulation during acute infection, a restricted number of CXC and CC chemokines are constitutively present in normal plasma at high concentrations. Here, such a chemotactic protein was purified to homogeneity from serum and fully identified as a novel CC chemokine by mass spectrometry and amino acid sequence analysis. The protein, tentatively designated Regakine-1, shows less than 50% sequence identity with any known chemokine. This novel CC chemokine chemoattracts both neutrophils and lymphocytes but not monocytes or eosinophils. Its modest chemotactic potency but high blood concentration is similar to that of other chemokines present in the circulation, such as hemofiltrate CC chemokine-1, platelet factor-4, and β-thromboglobulin. Regakine-1 did not induce neutrophil chemokinesis. However, it synergized with the CXC chemokines interleukin-8 and granulocyte chemotactic protein-2, and the CC chemokine monocyte chemotactic protein-3, resulting in an at least a 2-fold increase of the neutrophil and lymphocyte chemotactic response, respectively. The biologic effects of homogeneous natural Regakine-1 were confirmed with chemically synthesized chemokine. Like other plasma chemokines, it is expected that Regakine-1 plays a unique role in the circulation during normal or pathologic conditions.
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Palomino, Diana Carolina Torres, and Luciana Cavalheiro Marti. "Chemokines and immunity." Einstein (São Paulo) 13, no. 3 (September 2015): 469–73. http://dx.doi.org/10.1590/s1679-45082015rb3438.
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Chemokines are a large family of small cytokines and generally have low molecular weight ranging from 7 to 15kDa. Chemokines and their receptors are able to control the migration and residence of all immune cells. Some chemokines are considered pro-inflammatory, and their release can be induced during an immune response at a site of infection, while others are considered homeostatic and are involved in controlling of cells migration during tissue development or maintenance. The physiologic importance of this family of mediators is resulting from their specificity − members of the chemokine family induce recruitment of well-defined leukocyte subsets. There are two major chemokine sub-families based upon cysteine residues position: CXC and CC. As a general rule, members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and sub-set of lymphocytes, although there are some exceptions. This review discusses the potential role of chemokines in inflammation focusing on the two best-characterized chemokines: monocyte chemoattractant protein-1, a CC chemokine, and interleukin-8, a member of the CXC chemokine sub-family.
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Tomankova, Tereza, Eva Kriegova, and Mingyao Liu. "Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 7 (April 1, 2015): L603—L618. http://dx.doi.org/10.1152/ajplung.00203.2014.
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Chemokine receptors and their chemokine ligands, key mediators of inflammatory and immune cell trafficking, are involved in the regulation of both physiological and pathological processes in the lung. The discovery that chemokine receptors/chemokines, typically expressed by inflammatory and immune cells, are also expressed in structural lung tissue cells suggests their role in mediating the restoration of lung tissue structure and functions. Thus, chemokine receptors/chemokines contribute not only to inflammatory and immune responses in the lung but also play a critical role in the regulation of lung tissue repair, regeneration, and remodeling. This review aims to summarize current state-of-the-art on chemokine receptors and their ligands in lung diseases such as chronic obstructive pulmonary disease, asthma/allergy, pulmonary fibrosis, acute lung injury, and lung infection. Furthermore, the therapeutic opportunities of chemokine receptors in aforementioned lung diseases are discussed. The review also aims to delineate the potential contribution of chemokine receptors to the processes leading to repair/regeneration of the lung tissue.
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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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Jensen, Kristian K., Shu-Cheng Chen, R. William Hipkin, Maria T. Wiekowski, Martin A. Schwarz, Chuan-Chu Chou, J. Pedro Simas, Antonio Alcami, and Sergio A. Lira. "Disruption of CCL21-Induced Chemotaxis In Vitro and In Vivo by M3, a Chemokine-Binding Protein Encoded by Murine Gammaherpesvirus 68." Journal of Virology 77, no. 1 (January 1, 2003): 624–30. http://dx.doi.org/10.1128/jvi.77.1.624-630.2003.
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ABSTRACT Chemokine-binding proteins represent a novel class of antichemokine agents encoded by poxviruses and herpesviruses. One such protein is encoded by the M3 gene present in the murine gammaherpesvirus 68 (MHV-68) genome. The M3 gene encodes a secreted 44-kDa protein that binds with high affinity to certain murine and human chemokines and has been shown to block chemokine signaling in vitro. However, there has been no direct evidence that M3 blocks chemokine activity in vivo, nor has the nature of M3-chemokine interaction been defined. To better understand the ability of M3 to block chemokine activity in vivo, we examined its interaction with a specific subset of chemokines expressed in lymphoid tissues, areas where gammaherpesviruses characteristically establish latency. Here we show that M3 blocks in vitro chemotaxis induced by CCL19 and CCL21, chemokines expressed constitutively in secondary lymphoid tissues. Moreover, we provide evidence that chemokine M3 binding exhibits positive cooperativity. In vivo, the expression of M3 in the pancreas of transgenic mice inhibits recruitment of lymphocytes induced by transgenic expression of CCL21 in this organ. The ability of M3 to block the biological activity of chemokines may represent an important strategy used by MHV-68 to evade immune detection and favor viral replication in the infected host.
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Campbell, James J., Junliang Pan, and Eugene C. Butcher. "Cutting Edge: Developmental Switches in Chemokine Responses During T Cell Maturation." Journal of Immunology 163, no. 5 (September 1, 1999): 2353–57. http://dx.doi.org/10.4049/jimmunol.163.5.2353.
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Abstract We show that developmental transitions during thymocyte maturation are associated with dramatic changes in chemotactic responses to chemokines. Macrophage-derived chemokine, a chemokine expressed in the thymic medulla, attracts thymocytes only during a brief window of development, between the late cortical and early medullary stages. All medullary phenotypes (CD4 or CD8 single positive) but not immature thymocytes respond to the medullary stroma-expressed (and secondary lymphoid tissue-associated) chemokines secondary lymphoid-tissue chemokine and macrophage inflammatory protein-3β. The appearance of these responses is associated with the phenotypic stage of cortex to medulla migration and with up-regulation of mRNA for the receptors CCR4 (for macrophage-derived chemokine and thymus and activation-regulated chemokine) and CCR7 (for secondary lymphoid-tissue chemokine and macrophage inflammatory protein-3β). In contrast, most immature and medullary thymocytes migrate to thymus-expressed chemokine, an ability that is lost only with up-regulation of the peripheral homing receptor L-selectin during the latest stages of thymocyte maturation associated with export to the periphery. Developmental switches in chemokine responses may help regulate critical migratory events during T cell development.
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Chensue, Stephen W. "Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions." Clinical Microbiology Reviews 14, no. 4 (October 1, 2001): 821–35. http://dx.doi.org/10.1128/cmr.14.4.821-835.2001.
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SUMMARY Chemokines and their G-protein-coupled receptors represent an ancient and complex system of cellular communication participating in growth, development, homeostasis and immunity. Chemokine production has been detected in virtually every microbial infection examined; however, the precise role of chemokines is still far from clear. In most cases they appear to promote host resistance by mobilizing leukocytes and activating immune functions that kill, expel, or sequester pathogens. In other cases, the chemokine system has been pirated by pathogens, especially protozoa and viruses, which have exploited host chemokine receptors as modes of cellular invasion or developed chemokine mimics and binding proteins that act as antagonists or inappropriate agonists. Understanding microbial mechanisms of chemokine evasion will potentially lead to novel antimicrobial and anti-inflammatory therapeutic agents.
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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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Alexander-Brett, Jennifer M., and Daved H. Fremont. "Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor." Journal of Experimental Medicine 204, no. 13 (December 10, 2007): 3157–72. http://dx.doi.org/10.1084/jem.20071677.
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Viruses have evolved a myriad of evasion strategies focused on undermining chemokine-mediated immune surveillance, exemplified by the mouse γ-herpesvirus 68 M3 decoy receptor. Crystal structures of M3 in complex with C chemokine ligand 1/lymphotactin and CC chemokine ligand 2/monocyte chemoattractant protein 1 reveal that invariant chemokine features associated with G protein–coupled receptor binding are primarily recognized by the decoy C-terminal domain, whereas the N-terminal domain (NTD) reconfigures to engage divergent basic residue clusters on the surface of chemokines. Favorable electrostatic forces dramatically enhance the association kinetics of chemokine binding by M3, with a primary role ascribed to acidic NTD regions that effectively mimic glycosaminoglycan interactions. Thus, M3 employs two distinct mechanisms of chemical imitation to potently sequester chemokines, thereby inhibiting chemokine receptor binding events as well as the formation of chemotactic gradients necessary for directed leukocyte trafficking.
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Cheng, Nai-Lin, Xiaochun Chen, Cuong Nguyen, and Nan-ping Weng. "MicroRNAs modulate chemokine expression in naïve CD8 T cells (44.19)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 44.19. http://dx.doi.org/10.4049/jimmunol.188.supp.44.19.
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Abstract Chemokines play a pivotal role in regulating T cell function and migration in a space- and time-tight fashion. With aging, the levels of several chemokines alter in serum and have detrimental impact on the immune function. However, the mechanisms that regulate chemokine expressions and their age-associated alteration are not fully understood. MicroRNAs (miRNA) are key regulators for gene expression at the posttranscriptional level but their roles in the age-associated change of gene expression in T cells have not been examined. We sought to understand the role of miRNA in regulation of chemokine expression in CD8 T cells by profiling chemokines and miRNAs in naïve and memory CD8 T cells. Six miRNAs (miR-99a, -125b, -186, -335, -424, and -542-5p) were highly expressed in naïve CD8 T cells. In addition, we found that miR-125b, -335, and -186 have a putative binding site in the 3’ UTR of CC chemokine ligand 4 (CCL4), CCL5, and CXC chemokine ligand 5 (CXCL5), respectively. These chemokines are highly expressed in activated T cells and increased serum levels with age. Currently, we are testing these individual miRNA in the chemokine-reporter transfected Jurkat cells and in human primary CD8 T cells from young (≤ 30 yrs) and old (≥ 70yrs) donors. Our preliminary findings suggest that miRNA regulates chemokine expression in CD8 T cells and such regulation may change with age.
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Pontejo, Sergio M., Philip M. Murphy, and James E. Pease. "Chemokine Subversion by Human Herpesviruses." Journal of Innate Immunity 10, no. 5-6 (2018): 465–78. http://dx.doi.org/10.1159/000492161.
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Viruses use diverse molecular mechanisms to exploit and evade the immune response. Herpesviruses, in particular, encode functional chemokine and chemokine receptor homologs pirated from the host, as well as secreted chemokine-binding proteins with unique structures. Multiple functions have been described for herpesvirus chemokine components, including attraction of target cells, blockade of leukocyte migration, and modulation of gene expression and cell entry by the virus. Here we review current concepts about how human herpesvirus chemokines, chemokine receptors, and chemokine-binding proteins may be used to shape a proviral state in the host.
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Lim, Herman D., J. Robert Lane, Meritxell Canals, and Martin J. Stone. "Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10." International Journal of Molecular Sciences 22, no. 8 (April 19, 2021): 4232. http://dx.doi.org/10.3390/ijms22084232.
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Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the same receptor, a phenomenon known as biased agonism. The human CC chemokine receptors (CCRs) CCR4, CCR7 and CCR10 play important roles in T cell trafficking and have been reported to display biased agonism. To systematically characterize these effects, we analysed G protein- and β-arrestin-mediated signal transduction resulting from stimulation of these receptors by each of their cognate chemokine ligands within the same cellular background. Although the chemokines did not elicit ligand-biased agonism, the three receptors exhibited different arrays of signaling outcomes. Stimulation of CCR4 by either CC chemokine ligand 17 (CCL17) or CCL22 induced β-arrestin recruitment but not G protein-mediated signaling, suggesting that CCR4 has the potential to act as a scavenger receptor. At CCR7, both CCL19 and CCL21 stimulated G protein signaling and β-arrestin recruitment, with CCL19 consistently displaying higher potency. At CCR10, CCL27 and CCL28(4-108) stimulated both G protein signaling and β-arrestin recruitment, whereas CCL28(1-108) was inactive, suggesting that CCL28(4-108) is the biologically relevant form of this chemokine. These comparisons emphasize the intrinsic abilities of different receptors to couple with different downstream signaling pathways. Comparison of these results with previous studies indicates that differential agonism at these receptors may be highly dependent on the cellular context.
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Wu, X., G. J. Dolecki, B. Sherry, J. Zagorski, and J. B. Lefkowith. "Chemokines are expressed in a myeloid cell-dependent fashion and mediate distinct functions in immune complex glomerulonephritis in rat." Journal of Immunology 158, no. 8 (April 15, 1997): 3917–24. http://dx.doi.org/10.4049/jimmunol.158.8.3917.
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Abstract Using anti-glomerular basement membrane nephritis in rats, we investigated the mechanisms underlying in situ chemokine expression and the in vivo function of these cytokines during the acute phase of this model. We observed that CXC chemokine expression was monophasic and paralleled neutrophil (PMN) influx, whereas CC chemokine expression was biphasic with peaks coinciding with the influx of PMNs and macrophages (Mphi). The initial peak of chemokine expression was attenuated by decomplementation, neutropenia, and leukopenia, while the latter peak was attenuated only by leukopenia and augmented in the accelerated form of this disease model, corresponding to an increase in Mphi influx. Differential expression of chemokines by PMNs and Mphi was not an intrinsic property of these cells, as these leukocytes expressed similar profiles of chemokines in vitro. Immunostaining for Mphi inflammatory protein-1alpha, a CC chemokine, in acute nephritis validated that expression during acute nephritis was accompanied by local protein production. Moreover, neutralizing Ab to Mphi inflammatory protein-1alpha attenuated the acute phase proteinuria, but not the accompanying influx of PMNs. Neutralizing Ab to cytokine-induced neutrophil chemoattractant (a CXC chemokine), in comparison, inhibited both PMN influx and proteinuria. A combination of both Abs was not significantly more effective than either alone. In sum, the influx of myeloid cells is necessary for local chemokine expression in anti-glomerular basement membrane nephritis, although the differential expression of CXC and CC chemokines must involve additional factors. CXC and CC chemokines also mediate distinct, but overlapping, pathophysiologic roles in the acute phase of this model.
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Cheng, Wenjing, and Guangjie Chen. "Chemokines and Chemokine Receptors in Multiple Sclerosis." Mediators of Inflammation 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/659206.
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Multiple sclerosis is an autoimmune disease with classical traits of demyelination, axonal damage, and neurodegeneration. The migration of autoimmune T cells and macrophages from blood to central nervous system as well as the destruction of blood brain barrier are thought to be the major processes in the development of this disease. Chemokines, which are small peptide mediators, can attract pathogenic cells to the sites of inflammation. Each helper T cell subset expresses different chemokine receptors so as to exert their different functions in the pathogenesis of MS. Recently published results have shown that the levels of some chemokines and chemokine receptors are increased in blood and cerebrospinal fluid of MS patients. This review describes the advanced researches on the role of chemokines and chemokine receptors in the development of MS and discusses the potential therapy of this disease targeting the chemokine network.
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Kiguchi, Norikazu, Fumihiro Saika, Yuka Kobayashi, and Shiroh Kishioka. "Epigenetic regulation of CC-chemokine ligand 2 in nonresolving inflammation." Biomolecular Concepts 5, no. 4 (August 1, 2014): 265–73. http://dx.doi.org/10.1515/bmc-2014-0022.
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AbstractInflammation mediated by the crosstalk between leukocytes and resident tissue cells is crucial for the maintenance of homeostasis. Because chemokine ligands and receptors, which recruit a variety of leukocytes, are widely distributed among tissues, it is important to understand the mechanisms regulating inflammatory disease. Chemokines such as CC-chemokine ligand 2 (CCL2) amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leukocytes. Chemokine-dependent nonresolving inflammation occurs in the peripheral and central nervous systems, and underlies several intractable diseases, including cancer and neuropathic pain. The chronic upregulation of chemokines is often mediated by epigenetic mechanisms consisting of DNA methylation, histone modification, and nucleosome positioning. In particular, histone acetylation and methylation have been shown to play important roles in the upregulation of chemokine expression. In addition to CCL2, several other chemokines strongly contribute to neuropathic pain through epigenetic induction. Consequently, targeting epigenetic changes may have therapeutic potential for nonresolving inflammatory diseases such as neuropathic pain. Further research into the epigenetics of inflammatory diseases should promote the development of novel and effective treatment strategies for intractable inflammatory diseases.
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Greco, Giampaolo, Carl Mackewicz, and Jay A. Levy. "Sensitivity of human immunodeficiency virus infection to various α, β and γ chemokines." Journal of General Virology 80, no. 9 (September 1, 1999): 2369–73. http://dx.doi.org/10.1099/0022-1317-80-9-2369.
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Examination of a large panel of chemokines indicates that in addition to RANTES, MIP-1α and MIP-1β, the β-chemokine MCP-2 and, to a lesser extent, the γ-chemokine lymphotactin also show anti-human immunodeficiency virus (HIV) activity in cell culture. The amount of chemokine needed to suppress HIV replication by ≤50% was generally greater (≤250 ng/ml) than that required for inhibition of virus infection by RANTES, MIP-1α and MIP-1β. The β-chemokine MCP-3 was found to enhance the replication of both non-syncytium-inducing (NSI) and syncytium-inducing (SI) viruses at high concentrations (0·5–5 μg/ml). In contrast to a previous report, macrophage-derived chemokine was not found to inhibit HIV replication of either NSI or SI viruses, but at low concentrations enhanced NSI virus replication. When small amounts of RANTES or MCP-2 were added together with high concentrations of non-inhibitory chemokines, the anti-HIV effects were countered. Information on chemokines that affect HIV infection could be useful for future therapeutic strategies.
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Szekanecz, Zoltan. "Chemokines and chemokine receptors in arthritis." Frontiers in Bioscience S2, no. 1 (2010): 153–67. http://dx.doi.org/10.2741/s53.
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Bonecchi, Raffaella. "Chemokines and chemokine receptors: an overview." Frontiers in Bioscience Volume, no. 14 (2009): 540. http://dx.doi.org/10.2741/3261.
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Egido, Jesús. "Chemokines, chemokine receptors and renal disease." Kidney International 56, no. 1 (July 1999): 347–48. http://dx.doi.org/10.1046/j.1523-1755.1999.00551.x.
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Nelson, Peter J., and Alan M. Krensky. "Chemokines, Chemokine Receptors, and Allograft Rejection." Immunity 14, no. 4 (April 2001): 377–86. http://dx.doi.org/10.1016/s1074-7613(01)00118-2.
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Yamamoto, Toshiyuki. "Chemokines and Chemokine Receptors in Scleroderma." International Archives of Allergy and Immunology 140, no. 4 (2006): 345–56. http://dx.doi.org/10.1159/000094242.
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Kakinuma, T. "Chemokines, chemokine receptors, and cancer metastasis." Journal of Leukocyte Biology 79, no. 4 (January 13, 2006): 639–51. http://dx.doi.org/10.1189/jlb.1105633.
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Karpus, William J., and Brian T. Fife. "Keystone Symposia: chemokines and chemokine receptors." Expert Opinion on Biological Therapy 1, no. 3 (May 2001): 549–53. http://dx.doi.org/10.1517/14712598.1.3.549.
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