To see the other types of publications on this topic, follow the link: Chemokine receptor.
Journal articles on the topic 'Chemokine receptor'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Chemokine receptor.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
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.
Full textAbstract:
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.
2
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.
Full textAbstract:
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.
3
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.
Full textAbstract:
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.
4
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.
Full textAbstract:
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.
5
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.
Full textAbstract:
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.
6
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.
Full textAbstract:
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.
7
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.
Full textAbstract:
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.
8
Sanchez, Julie, J. Robert Lane, Meritxell Canals, and Martin J. Stone. "Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1." International Journal of Molecular Sciences 20, no. 10 (May 15, 2019): 2417. http://dx.doi.org/10.3390/ijms20102417.
Full textAbstract:
Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from β-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and β-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.
9
Huang, Ziwei, Santosh Kumar, Won-Tak Choi, Navid Madani, Chang-Zhi Dong, Dongxiang Liu, Jun Wang, Jing An, and Joseph G. Sodroski. "A New Class of Chemokine Analogs as Useful Research Tools to Study Chemokine Receptor Function and Promising Therapeutic Agents." Blood 104, no. 11 (November 16, 2004): 3839. http://dx.doi.org/10.1182/blood.v104.11.3839.3839.
Full textAbstract:
Abstract Chemokine receptors play important roles in many physiological processes and are implicated in a wide range of human diseases including acute respiratory distress syndrome, allergic asthma, psoriasis, arthritis, multiple sclerosis, cancer, atherosclerosis and most notably AIDS. To enable the applications of chemokine ligands as probes of receptor biology and pharmacology, and inhibitors of diseases mediated by chemokine receptors, a major problem with the lack of receptor selectivity of these natural chemokines must be overcome. In this study, we have developed a chemical approach combining total protein synthesis and modular modifications to generate a new family of unnatural chemokines termed SMM-chemokines (which refer to synthetically and modularly modified chemokines) with designed receptor selectivity and affinity. A proof of the concept has been provided by applying this strategy to transform a very nonselective chemokine vMIP-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for HIV-1 entry. Such novel molecules have been shown subsequently to be valuable probes in gaining insights into receptor binding and signaling mechanisms, and as potent inhibitors to prevent HIV-1 entry and infection. These results strongly support the design concept of these SMM-chemokines and suggest that general applicability of this approach for studying and controlling other chemokine receptors and the diseases they mediate might be anticipated.
10
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.
Full textAbstract:
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.
11
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.
Full textAbstract:
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.
12
Sun, Jia, Raina Devi Ramnath, and Madhav Bhatia. "Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils." American Journal of Physiology-Cell Physiology 293, no. 2 (August 2007): C696—C704. http://dx.doi.org/10.1152/ajpcell.00060.2007.
Full textAbstract:
Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 μM) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SP primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-1α/CCL3. The activating effect of SP on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-1R antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SP-induced chemokine upregulation was NF-κB dependent. SP time dependently induced NF-κB p65 binding activity, IκBα degradation, and NF-κB p65 nuclear translocation in neutrophils. Inhibition of NF-κB activation with its inhibitor Bay11-7082 (10 μM) abolished SP-induced NF-κB binding activity and upregulation of MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-κB activation.
13
Murdoch, Craig, and Adam Finn. "Chemokine receptors and their role in inflammation and infectious diseases." Blood 95, no. 10 (May 15, 2000): 3032–43. http://dx.doi.org/10.1182/blood.v95.10.3032.
Full textAbstract:
Abstract Chemokines are small peptides that are potent activators and chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein–coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the observation that some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss structural and functional aspects of chemokine receptor biology and will consider the roles these receptors play in inflammation and in infectious diseases.
14
Murdoch, Craig, and Adam Finn. "Chemokine receptors and their role in inflammation and infectious diseases." Blood 95, no. 10 (May 15, 2000): 3032–43. http://dx.doi.org/10.1182/blood.v95.10.3032.010k17_3032_3043.
Full textAbstract:
Chemokines are small peptides that are potent activators and chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein–coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the observation that some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss structural and functional aspects of chemokine receptor biology and will consider the roles these receptors play in inflammation and in infectious diseases.
15
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.
Full textAbstract:
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.
16
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.
Full textAbstract:
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.
17
Neote, K., JY Mak, LF Jr Kolakowski, and TJ Schall. "Functional and biochemical analysis of the cloned Duffy antigen: identity with the red blood cell chemokine receptor." Blood 84, no. 1 (July 1, 1994): 44–52. http://dx.doi.org/10.1182/blood.v84.1.44.44.
Full textAbstract:
Abstract The Duffy blood group antigen has been postulated to be a receptor on red blood cells (RBCs) for the malarial parasite Plasmodium vivax and a promiscuous receptor for the chemokine superfamily of inflammatory proteins. Recently, the Duffy antigen glycoprotein D cDNA has been cloned (Chaudhuri et al: Proc Natl Acad Sci USA 90:10793, 1993). We have analyzed the binding properties of the cloned Duffy antigen. Duffy- antigen cDNAs expressed in human embryonic kidney cells produced cell- surface proteins that reacted with two known anti-Duffy monoclonal antibodies. Direct ligand binding and displacement experiments using recombinant chemokine proteins also show that the cloned Duffy protein is the RBC chemokine receptor. Radiolabeled chemokines of both the C-C (RANTES and MCP-1) and C-X-C (IL-8 and MGSA/gro) subclasses bound reversibly to transfected cells with dissociation constants in the nanomolar range. Chemokines of either class displaced heterologous chemokines, indicating that they were competing for a single site on the transfected cells. Although the chemokines bound to the transfected cells with high affinity, there was no evidence for signal transduction, as measured by transient increases in intracellular calcium ion concentration, through the Duffy antigen/RBC chemokine receptor in transfected cells. Lastly, we have performed a computer analysis on the amino acid structure of the Duffy antigen/RBC chemokine receptor. Although the cloned Duffy antigen has been postulated to be a nine-transmembrane-spanning receptor, our analysis suggests that the molecule most likely belongs to the seven-transmembrane-spanning receptor superfamily and is therefore similar to other chemokine receptors previously identified.
18
Neote, K., JY Mak, LF Jr Kolakowski, and TJ Schall. "Functional and biochemical analysis of the cloned Duffy antigen: identity with the red blood cell chemokine receptor." Blood 84, no. 1 (July 1, 1994): 44–52. http://dx.doi.org/10.1182/blood.v84.1.44.bloodjournal84144.
Full textAbstract:
The Duffy blood group antigen has been postulated to be a receptor on red blood cells (RBCs) for the malarial parasite Plasmodium vivax and a promiscuous receptor for the chemokine superfamily of inflammatory proteins. Recently, the Duffy antigen glycoprotein D cDNA has been cloned (Chaudhuri et al: Proc Natl Acad Sci USA 90:10793, 1993). We have analyzed the binding properties of the cloned Duffy antigen. Duffy- antigen cDNAs expressed in human embryonic kidney cells produced cell- surface proteins that reacted with two known anti-Duffy monoclonal antibodies. Direct ligand binding and displacement experiments using recombinant chemokine proteins also show that the cloned Duffy protein is the RBC chemokine receptor. Radiolabeled chemokines of both the C-C (RANTES and MCP-1) and C-X-C (IL-8 and MGSA/gro) subclasses bound reversibly to transfected cells with dissociation constants in the nanomolar range. Chemokines of either class displaced heterologous chemokines, indicating that they were competing for a single site on the transfected cells. Although the chemokines bound to the transfected cells with high affinity, there was no evidence for signal transduction, as measured by transient increases in intracellular calcium ion concentration, through the Duffy antigen/RBC chemokine receptor in transfected cells. Lastly, we have performed a computer analysis on the amino acid structure of the Duffy antigen/RBC chemokine receptor. Although the cloned Duffy antigen has been postulated to be a nine-transmembrane-spanning receptor, our analysis suggests that the molecule most likely belongs to the seven-transmembrane-spanning receptor superfamily and is therefore similar to other chemokine receptors previously identified.
19
Isaikina, Polina, Ching-Ju Tsai, Nikolaus Dietz, Filip Pamula, Anne Grahl, Kenneth N. Goldie, Ramon Guixà-González, et al. "Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist." Science Advances 7, no. 25 (June 2021): eabg8685. http://dx.doi.org/10.1126/sciadv.abg8685.
Full textAbstract:
The human CC chemokine receptor 5 (CCR5) is a G protein–coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.
20
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.
Full textAbstract:
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.
21
Horuk, R., A. W. Martin, Z. Wang, L. Schweitzer, A. Gerassimides, H. Guo, Z. Lu, et al. "Expression of chemokine receptors by subsets of neurons in the central nervous system." Journal of Immunology 158, no. 6 (March 15, 1997): 2882–90. http://dx.doi.org/10.4049/jimmunol.158.6.2882.
Full textAbstract:
Abstract IL-8 is expressed by activated and neoplastic astrocytes and enhances the survival of hippocampal neurons in vitro. Since mRNA encoding chemokine receptors have been demonstrated in brain, the expression of chemokine receptors by specific cell types in anatomic regions of the central nervous system (CNS) was investigated. Archival tissues from various regions of the CNS were stained with specific mAbs to the Duffy Ag/receptor for chemokines, a promiscuous receptor that binds selected chemokines; the specific receptor for IL-8 (CXCR1); and the receptor (CXCR2) shared by IL-8 and melanoma growth stimulatory activity. The Duffy Ag/receptor for chemokines was expressed exclusively by Purkinje cells in the cerebellum. Chemokine binding and radioligand cross-linking confirmed the presence of a high affinity, promiscuous chemokine receptor in the cerebellum. Although CXCR1 was not expressed in the CNS, CXCR2 was expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord. Fibers that express CXCR2 included those in the superior cerebellar peduncle and the substantia gelatinosa. Immunohistochemical analysis of the involved brain tissues from patients with Alzheimer's disease revealed expression of CXCR2 in the neuritic portion of plaques surrounding deposits of amyloid. These data suggest that chemokines may play a role in reactive processes in normal neuronal function and neurodegenerative disorders.
22
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.
Full textAbstract:
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.
23
Liu, Dongxiang, Navid Madani, Ying Li, Rong Cao, Won-Tak Choi, Sameer P. Kawatkar, Mi Youn Lim, et al. "Crystal Structure and Structural Mechanism of a Novel Anti-Human Immunodeficiency Virus and d-Amino Acid-Containing Chemokine." Journal of Virology 81, no. 20 (August 8, 2007): 11489–98. http://dx.doi.org/10.1128/jvi.02845-06.
Full textAbstract:
ABSTRACT Chemokines and their receptors play important roles in normal physiological functions and the pathogeneses of a wide range of human diseases, including the entry of human immunodeficiency virus type 1 (HIV-1). However, the use of natural chemokines to probe receptor biology or to develop therapeutic drugs is limited by their lack of selectivity and the poor understanding of mechanisms in ligand-receptor recognition. We addressed these issues by combining chemical and structural biology in research into molecular recognition and inhibitor design. Specifically, the concepts of chemical biology were used to develop synthetically and modularly modified (SMM) chemokines that are unnatural and yet have properties improved over those of natural chemokines in terms of receptor selectivity, affinity, and the ability to explore receptor functions. This was followed by using structural biology to determine the structural basis for synthetically perturbed ligand-receptor selectivity. As a proof-of-principle for this combined chemical and structural-biology approach, we report a novel d-amino acid-containing SMM-chemokine designed based on the natural chemokine called viral macrophage inflammatory protein II (vMIP-II). The incorporation of unnatural d-amino acids enhanced the affinity of this molecule for CXCR4 but significantly diminished that for CCR5 or CCR2, thus yielding much more selective recognition of CXCR4 than wild-type vMIP-II. This d-amino acid-containing chemokine also showed more potent and specific inhibitory activity against HIV-1 entry via CXCR4 than natural chemokines. Furthermore, the high-resolution crystal structure of this d-amino acid-containing chemokine and a molecular-modeling study of its complex with CXCR4 provided the structure-based mechanism for the selective interaction between the ligand and chemokine receptors and the potent anti-HIV activity of d-amino acid-containing chemokines.
24
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.
Full textAbstract:
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.
25
Borroni, E. M., C. Buracchi, Y. Martinez de la Torre, E. Galliera, A. Vecchi, R. Bonecchi, A. Mantovani, and M. Locati. "The chemoattractant decoy receptor D6 as a negative regulator of inflammatory responses." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1014–17. http://dx.doi.org/10.1042/bst0341014.
Full textAbstract:
Other than signalling receptors sustaining leucocyte recruitment during inflammatory reactions, the chemokine system includes ‘silent’ receptors with distinct specificity and tissue distribution. The best-characterized molecule of this subgroup is the CC chemokine receptor D6, which binds most inflammatory CC chemokines and targets them to degradation via constitutive ligand-independent internalization. Structure–function analysis and recent results with gene-targeted animals indicate that D6 has unique functional and structural features, which make it ideally adapted to act as a chemokine decoy and scavenger receptor, strategically located on lymphatic endothelium and placenta to dampen inflammation in tissues and draining lymph nodes.
26
Wise, E., and J. E. Pease. "Unravelling the mechanisms underpinning chemokine receptor activation and blockade by small molecules: a fine line between agonism and antagonism?" Biochemical Society Transactions 35, no. 4 (July 20, 2007): 755–59. http://dx.doi.org/10.1042/bst0350755.
Full textAbstract:
Chemokines are a family of small basic proteins which induce the directed migration of cells, notably leucocytes, by binding to specific GPCRs (G-protein-coupled receptors). Both chemokines and their receptors have been implicated in a host of clinically important diseases, leading to the notion that antagonism of the chemokine–chemokine receptor network may be therapeutically advantageous. Consequently, considerable effort has been put into the development of small-molecule antagonists of chemokine receptors and several such compounds have been described in the literature. One curious by-product of this activity has been the description of several small-molecule agonists of the receptors, which are typically discovered following the optimization of lead antagonists. In this review we discuss these findings and conclude that these small-molecule agonists might be exploited to further our understanding of the molecular mechanisms by which chemokine receptors are activated.
27
Sallusto, Federica, Danielle Lenig, Charles R. Mackay, and Antonio Lanzavecchia. "Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes." Journal of Experimental Medicine 187, no. 6 (March 16, 1998): 875–83. http://dx.doi.org/10.1084/jem.187.6.875.
Full textAbstract:
Chemokines and their receptors are important elements for the selective attraction of various subsets of leukocytes. To better understand the selective migration of functional subsets of T cells, chemokine receptor expression was analyzed using monoclonal antibodies, RNase protection assays, and the response to distinct chemokines. Naive T cells expressed only CXC chemokine receptor (CXCR)4, whereas the majority of memory/activated T cells expressed CXCR3, and a small proportion expressed CC chemokine receptor (CCR)3 and CCR5. When polarized T cell lines were analyzed, CXCR3 was found to be expressed at high levels on T helper cell (Th)0s and Th1s and at low levels on Th2s. In contrast, CCR3 and CCR4 were found on Th2s. This was confirmed by functional responses: only Th2s responded with an increase in [Ca2+]i to the CCR3 and CCR4 agonists eotaxin and thymus and activation regulated chemokine (TARC), whereas only Th0s and Th1s responded to low concentrations of the CXCR3 agonists IFN-γ–inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig). Although CCR5 was expressed on both Th1 and Th2 lines, it was absent in several Th2 clones and its expression was markedly influenced by interleukin 2. Chemokine receptor expression and association with Th1 and Th2 phenotypes was affected by other cytokines present during polarization. Transforming growth factor β inhibited CCR3, but enhanced CCR4 and CCR7 expression, whereas interferon α inhibited CCR3 but upregulated CXCR3 and CCR1. These results demonstrate that chemokine receptors are markers of naive and polarized T cell subsets and suggest that flexible programs of chemokine receptor gene expression may control tissue-specific migration of effector T cells.
28
Post, T. W., C. R. Bozic, M. E. Rothenberg, A. D. Luster, N. Gerard, and C. Gerard. "Molecular characterization of two murine eosinophil beta chemokine receptors." Journal of Immunology 155, no. 11 (December 1, 1995): 5299–305. http://dx.doi.org/10.4049/jimmunol.155.11.5299.
Full textAbstract:
Abstract beta or C-C chemokines including RANTES, MCP-3, MIP-1 alpha, and eotaxin have been implicated in the pathogenesis of eosinophilic inflammation. Two human beta chemokine receptors have been cloned and characterized: the MIP-1 alpha/RANTES receptor or C-C chemokine receptor 1 (CCR-1) and the MCP-1 receptor or C-C chemokine receptor 2 (CCR-2). However, no murine beta chemokine receptors have thus far been reported. Molecular cloning from mouse genomic DNA and cDNA libraries yielded two murine beta chemokine receptors with 79% and 65% sequence identity with human CCR-1, and 50% and 55% with human CCR-2. COS cells transiently transfected with the murine homologue of human CCR-1 bind murine MIP-1 alpha and human RANTES with Kds of 3.4 nM and 4.2 nM and murine MIP-1 beta with an EC50 of 8.9 nM. The other murine beta chemokine receptor, which we have designated murine CCR-3, also binds murine MIP-1 alpha. The mRNAs for both receptors are expressed in eosinophils from IL-5 transgenic mice. The level of murine CCR-3 mRNA in these mouse eosinophils exceeds that of CCR-1 mRNA and approaches actin levels. Murine MIP-1 alpha was found to be a potent chemoattractant for murine eosinophils. Our findings suggest that the murine MIP-1 alpha ligand/receptor system is an important mediator of murine eosinophil trafficking.
29
Meissner, Anja, Olaf Zilles, Rosa Varona, Katrin Jozefowski, Uwe Ritter, Gabriel Marquez, Rupert Hallmann, and Heinrich Körner. "CC chemokine ligand 20 partially controls adhesion of naive B cells to activated endothelial cells under shear stress." Blood 102, no. 8 (October 15, 2003): 2724–27. http://dx.doi.org/10.1182/blood-2003-01-0007.
Full textAbstract:
Abstract Chemokines are thought to control lymphocyte recruitment to the inflamed endothelium. To dissect chemokine-mediated adhesion, binding of ex vivo isolated splenocytes to tumor necrosis factor (TNF)–activated endothelial cells was analyzed under shear stress. We observed specific adhesion of naive follicular B cells, which could be blocked by pertussis toxin. This indicated a G protein–mediated binding and pointed at a contribution of chemokine receptors to B-cell adhesion. Analysis of chemokines expressed by TNF-activated endothelial cells showed that CC chemokine ligand 2 (CCL2), CCL17, and CCL20 were up-regulated. Only on follicular B cells was the cognate receptor for CCL20, CC chemokine receptor 6 (CCR6), expressed strongly, and a functional transmigration assay with CCR6-negative B cells demonstrated conclusively the sole signaling of CCL20 through CCR6. Desensitization of CCR6 on naive B cells with CCL20 resulted in receptor down-regulation and reduced B-cell adhesion. We conclude that CCL20 plays a vital role in B-cell adhesion to the inflamed endothelium.
30
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.
Full textAbstract:
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.
31
Soriano, Silvia F., Patricia Hernanz-Falcón, José Miguel Rodríguez-Frade, Ana Martín de Ana, Ruth Garzón, Carla Carvalho-Pinto, Antonio J. Vila-Coro, et al. "Functional Inactivation of CXC Chemokine Receptor 4–mediated Responses through SOCS3 Up-regulation." Journal of Experimental Medicine 196, no. 3 (July 29, 2002): 311–21. http://dx.doi.org/10.1084/jem.20012041.
Full textAbstract:
Hematopoietic cell growth, differentiation, and chemotactic responses require coordinated action between cytokines and chemokines. Cytokines promote receptor oligomerization, followed by Janus kinase (JAK) kinase activation, signal transducers and transactivators of transcription (STAT) nuclear translocation, and transcription of cytokine-responsive genes. These include genes that encode a family of negative regulators of cytokine signaling, the suppressors of cytokine signaling (SOCS) proteins. After binding their specific receptors, chemokines trigger receptor dimerization and activate the JAK/STAT pathway. We show that SOCS3 overexpression or up-regulation, stimulated by a cytokine such as growth hormone, impairs the response to CXCL12, measured by Ca2+ flux and chemotaxis in vitro and in vivo. This effect is mediated by SOCS3 binding to the CXC chemokine receptor 4 receptor, blocking JAK/STAT and Gαi pathways, without interfering with cell surface chemokine receptor expression. The data provide clear evidence for signaling cross-talk between cytokine and chemokine responses in building a functional immune system.
32
Höpken, Uta E., Hans-Dieter Foss, Dagmar Meyer, Michael Hinz, Korinna Leder, Harald Stein, and Martin Lipp. "Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs." Blood 99, no. 4 (February 15, 2002): 1109–16. http://dx.doi.org/10.1182/blood.v99.4.1109.
Full textAbstract:
Chemokines and chemokine receptors are key mediators for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. It is also presumed that chemokines and their receptors are likely to play a critical role in the localization of malignant hematopoietic cells in their target organs. This study analyzed chemokine and chemokine receptor expression in several Hodgkin disease (HD)–derived cell lines and in HD tumors. All HD-derived cell lines expressed functional CCR7 and CXCR4 receptors. CCR7 up-regulation was mediated by constitutive NF-κB activity. Lymphoid tissues in HD revealed differential expression levels of CCR7, CXCR4, and CXCR5, depending on the distinct subtypes of HD. HD of the classical subtypes, predominantly located in the interfollicular zone, showed strong CCR7 and CXCR4 expression and moderate CXCR5 expression. In contrast, the nodular lymphocyte-predominant HD (NLP) subtype, regularly associated with follicular structures, exhibited no CCR7 reactivity but abundant CXCR4 staining. Their respective chemokine ligands showed marked expression by reactive cells within the tumors of classical HD and outside of the tumor nodules in NLPHD. Functionally, such differential chemokine receptor expression might contribute to specific localization and confinement of neoplastic cells within the target organs in the distinct HD entities.
33
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.
Full textAbstract:
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.
34
Rizeq, Balsam, and Mohammed Imad Malki. "The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression." Cancers 12, no. 4 (April 23, 2020): 1036. http://dx.doi.org/10.3390/cancers12041036.
Full textAbstract:
Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at the sites of metastatic disease. Chemokine receptors belong to the G-protein-coupled receptors (GPCRs) family that appear to be implicated in inflammatory diseases, tumor growth and metastasis. One of its members, C-C Chemokine receptor 7 (CCR7), binds chemokines CCL19 and CCL21, which are important for tissue homeostasis, immune surveillance and tumorigenesis. These receptors have been shown to induce the pathobiology of breast cancer due to their ability to induce cellular proliferation and migration upon the binding of the cognate chemokine receptors. The underlying signaling pathways and exact cellular interactions within this biological system are not fully understood and need further insights. Thus, in this review, we summarize the essential roles of CCR7 and its receptors in breast cancer progression. Furthermore, we discuss the mechanisms of regulation that may lead to novel opportunities for therapeutic intervention. Despite the enormous advances in our knowledge of the nature of the chemokines in breast cancer metastasis, research about the involvement of CCR7 in cancer progression is still limited. Therefore, further studies are essential to illustrate the distinct roles of CCR7 in cancer progression and validate its potential as a preventive bio-factor for human breast cancer metastasis by targeting chemokine receptor genes.
35
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.
Full textAbstract:
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.
36
Nieto, Marta, José M. R. Frade, David Sancho, Mario Mellado, Carlos Martinez-A, and Francisco Sánchez-Madrid. "Polarization of Chemokine Receptors to the Leading Edge during Lymphocyte Chemotaxis." Journal of Experimental Medicine 186, no. 1 (July 7, 1997): 153–58. http://dx.doi.org/10.1084/jem.186.1.153.
Full textAbstract:
Leukocyte migration in response to cell attractant gradients or chemotaxis is a key phenomenon both in cell movement and in the inflammatory response. Chemokines are quite likely to be the key molecules directing migration of leukocytes that involve cell polarization with generation of specialized cell compartments. The precise mechanism of leukocyte chemoattraction is not known, however. In this study, we demonstrate that the CC chemokine receptors CCR2 and CCR5, but not cytokine receptors such as interleukin (IL)-2Rα, IL-2Rβ, tumor necrosis factor receptor 1, or transforming growth factor βR, are redistributed to a pole in T cells that are migrating in response to chemokines. Immunofluorescence and confocal microscopy studies show that the chemokine receptors concentrate at the leading edge of the cell on the flattened cell-substratum contact area, induced specifically by the signals that trigger cell polarization. The redistribution of chemokine receptors is blocked by pertussis toxin and is dependent on cell adhesion through integrin receptors, which mediate cell migration. Chemokine receptor expression on the leading edge of migrating polarized lymphocytes appears to act as a sensor mechanism for the directed migration of leukocytes through a chemoattractant gradient.
37
Belay, Tesfaye, Francis O. Eko, Godwin A. Ananaba, Samera Bowers, Terri Moore, Deborah Lyn, and Joseph U. Igietseme. "Chemokine and Chemokine Receptor Dynamics during Genital Chlamydial Infection." Infection and Immunity 70, no. 2 (February 2002): 844–50. http://dx.doi.org/10.1128/iai.70.2.844-850.2002.
Full textAbstract:
ABSTRACT Current design strategies for vaccines against certain microbial pathogens, including Chlamydia trachomatis, require the induction and targeting of specific immune effectors to the local sites of infection known as the mucosal effector sites. Chemokines and their receptors are important mediators of leukocyte trafficking and of the controlled recruitment of specific leukocyte clonotypes during host defense against infections and during inflammation. We analyzed the dynamics of chemokine and chemokine receptor expression in genital mucosae during genital chlamydial infection in a murine model to determine how these molecular entities influence the development of immunity and the clearance of infection. A time course study revealed an increase of up to threefold in the levels of expression of RANTES, monocyte chemotactic protein 1 (MCP-1), gamma-interferon-inducible protein 10 (IP-10), macrophage inflammatory protein 1α (MIP-1α), and intercellular adhesion molecule type 1 (ICAM-1) after genital infection with the C. trachomatis agent of mouse pneumonitis. Peak levels of expression of RANTES, MCP-1, and MIP-1α occurred by day 7 after primary infection, while those of IP-10 and ICAM-1 peaked by day 21. Expression levels of these molecules decreased by day 42 after primary infection, by which time all animals had resolved the infection, suggesting an infection-driven regulation of expression. A rapid upregulation of expression of these molecules was observed after secondary infection. The presence of cells bearing the chemokine receptors CCR5 and CXCR3, known to be preferentially expressed on Th1 and dendritic cells, was also synchronous with the kinetics of immune induction in the genital tract and clearance of infection. Results demonstrated that genital chlamydial infection is associated with a significant induction of chemokines and chemokine receptors that are involved in the recruitment of Th1 cells into the site of infection. Future studies will focus on how selective modulation of chemokines and their receptors can be used to optimize long-term immunity against Chlamydia.
38
Umemura, Masayuki, Masatoshi Yamasaki, Toshiki Tamura, and Goro Matsuzaki. "Dispensable role of chemokine receptors in migration of mycobacterial antigen-specific CD4+ T cells into mycobacteria-infected lung." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 156.34. http://dx.doi.org/10.4049/jimmunol.204.supp.156.34.
Full textAbstract:
Abstract Mycobacterial antigen-specific CD4+ Th1 cells have a pivotal role in protective immunity against mycobacterial infections, including pulmonary tuberculosis. In the course of infection, Th1 cells differentiate in the lung-draining lymph nodes and migrate into the infected lung. Chemokine receptors on T cells are involved in T cell migration into the intestine and skin. However, the role of chemokine receptors in the migration of CD4+ T cells into the lung has not yet been determined. To address this issue, the role of chemokine receptors in T cell migration into the mycobacteria-infected lung was analyzed using mycobacterial Ag85B peptide 25-specific T cell receptor-transgenic (P25) CD4+ T cells. P25 T cells in the Mycobacterium bovis BCG-infected lung and lung-draining mediastinal lymph nodes (MedLN) expressed the chemokine receptors, CCR5, CCR6, CXCR3, and CXCR5, which bind chemokines produced by the BCG-infected lung. To further analyze the role of chemokine receptors in the migration of BCG-primed P25 T cells into the lung and medLN, P25 T cells were adoptively transferred into BCG-infected wild-type mice and their migration into the lung was monitored. Unexpectedly, blocking chemokine receptor function with pertussis toxin, a G-protein inhibitor, failed to suppress migration of T cells into the infected lung. However, the treatment completely blocked migration of the MedLN P25 T cells into the recipient lymph node. These results suggest that the interaction of chemokine receptors on mycobacterial antigen-specific Th1 cells with chemokines is dispensable for their migration into the mycobacteria-infected lung.
39
Rabin, Ronald L., Matthew K. Park, Fang Liao, Ruth Swofford, David Stephany, and Joshua M. Farber. "Chemokine Receptor Responses on T Cells Are Achieved Through Regulation of Both Receptor Expression and Signaling." Journal of Immunology 162, no. 7 (April 1, 1999): 3840–50. http://dx.doi.org/10.4049/jimmunol.162.7.3840.
Full textAbstract:
Abstract To address the issues of redundancy and specificity of chemokines and their receptors in lymphocyte biology, we investigated the expression of CC chemokine receptors CCR1, CCR2, CCR3, CCR5, CXCR3, and CXCR4 and responses to their ligands on memory and naive, CD4 and CD8 human T cells, both freshly isolated and after short term activation in vitro. Activation through CD3 for 3 days had the most dramatic effects on the expression of CXCR3, which was up-regulated and functional on all T cell populations including naive CD4 cells. In contrast, the effects of short term activation on expression of other chemokine receptors was modest, and expression of CCR2, CCR3, and CCR5 on CD4 cells was restricted to memory subsets. In general, patterns of chemotaxis in the resting cells and calcium responses in the activated cells corresponded to the patterns of receptor expression among T cell subsets. In contrast, the pattern of calcium signaling among subsets of freshly isolated cells did not show a simple correlation with receptor expression, so the propensity to produce a global rise in the intracellular calcium concentration differed among the various receptors within a given T cell subset and for an individual receptor depending on the cell where it was expressed. Our data suggest that individual chemokine receptors and their ligands function on T cells at different stages of T cell activation/differentiation, with CXCR3 of particular importance on newly activated cells, and demonstrate T cell subset-specific and activation state-specific responses to chemokines that are achieved by regulating receptor signaling as well as receptor expression.
40
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.
Full textAbstract:
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.
41
Cardona, Astrid E., Margaret E. Sasse, Liping Liu, Sandra M. Cardona, Makiko Mizutani, Carine Savarin, Taofang Hu, and Richard M. Ransohoff. "Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues." Blood 112, no. 2 (July 15, 2008): 256–63. http://dx.doi.org/10.1182/blood-2007-10-118497.
Full textAbstract:
Abstract In vitro studies have implicated chemokine receptors in consumption and clearance of specific ligands. We studied the role that various signaling chemokine receptors play during ligand homeostasis in vivo. We examined the levels of ligands in serum and CNS tissue in mice lacking chemokine receptors. Compared with receptor-sufficient controls, Cx3cr1−/− mice exhibited augmented levels of CX3CL1 both in serum and brain, and circulating levels of CXCL1 and CXCL2 were increased in Cxcr2−/− mice. CCR2-deficient mice showed significantly increased amounts of circulating CCL2 compared with wild-type mice. Cxcr3−/− mice revealed increased levels of circulating and brain CXCL10 after experimental autoimmune encephalomyelitis (EAE) induction. CCR2-deficient peripheral blood and resident peritoneal cells exhibited reduced binding capacity and biologic responses to the CCR1 ligand CCL3, suggesting that elevated levels of CCR2 ligands had down-regulated CCR1. The results indicate that signaling chemokine receptors clear chemokines from circulation and tissues. These homeostatic functions of signaling chemokine receptors need to be integrated into safety and efficacy calculations when considering therapeutic receptor blockade.
42
Isci, Damla, Giulia D’Uonnolo, May Wantz, Bernard Rogister, Arnaud Lombard, Andy Chevigné, Martyna Szpakowska, and Virginie Neirinckx. "Patient-Oriented Perspective on Chemokine Receptor Expression and Function in Glioma." Cancers 14, no. 1 (December 28, 2021): 130. http://dx.doi.org/10.3390/cancers14010130.
Full textAbstract:
Gliomas are severe brain malignancies, with glioblastoma (GBM) being the most aggressive one. Despite continuous efforts for improvement of existing therapies, overall survival remains poor. Over the last years, the implication of chemokines and their receptors in GBM development and progression has become more evident. Recently, large amounts of clinical data have been made available, prompting us to investigate chemokine receptors in GBM from a still-unexplored patient-oriented perspective. This study aims to highlight and discuss the involvement of chemokine receptors—CCR1, CCR5, CCR6, CCR10, CX3CR1, CXCR2, CXCR4, ACKR1, ACKR2, and ACKR3—most abundantly expressed in glioma patients based on the analysis of publicly available clinical datasets. Given the strong intratumoral heterogeneity characterizing gliomas and especially GBM, receptor expression was investigated by glioma molecular groups, by brain region distribution, emphasizing tissue-specific receptor functions, and by cell type enrichment. Our study constitutes a clinically relevant and patient-oriented guide that recapitulates the expression profile and the complex roles of chemokine receptors within the highly diversified glioma landscape. Additionally, it strengthens the importance of patient-derived material for development and precise amelioration of chemokine receptor-targeting therapies.
43
Semple, Bridgette D., Thomas Kossmann, and Maria Cristina Morganti-Kossmann. "Role of Chemokines in CNS Health and Pathology: A Focus on the CCL2/CCR2 and CXCL8/CXCR2 Networks." Journal of Cerebral Blood Flow & Metabolism 30, no. 3 (November 11, 2009): 459–73. http://dx.doi.org/10.1038/jcbfm.2009.240.
Full textAbstract:
Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.
44
Dyskova, Tereza, Regina Fillerova, Tomas Novosad, Milos Kudelka, Monika Zurkova, Petr Gajdos, Vitezslav Kolek, and Eva Kriegova. "Correlation Network Analysis Reveals Relationships between MicroRNAs, Transcription FactorT-bet, and Deregulated Cytokine/Chemokine-Receptor Network in Pulmonary Sarcoidosis." Mediators of Inflammation 2015 (2015): 1–16. http://dx.doi.org/10.1155/2015/121378.
Full textAbstract:
Sarcoidosis is an inflammatory granulomatous disease with unknown etiology driven by cytokines and chemokines. There is limited information regarding the regulation of cytokine/chemokine-receptor network in bronchoalveolar lavage (BAL) cells in pulmonary sarcoidosis, suggesting contribution of miRNAs and transcription factors. We therefore investigated gene expression of 25 inflammation-related miRNAs, 27 cytokines/chemokines/receptors, and a Th1-transcription factorT-betin unseparated BAL cells obtained from 48 sarcoidosis patients and 14 control subjects using quantitative RT-PCR. We then examined both miRNA-mRNA expressions to enrich relevant relationships. This first study on miRNAs in sarcoid BAL cells detected deregulation ofmiR-146a,miR-150,miR-202,miR-204, andmiR-222expression comparing to controls. Subanalysis revealed higher number ofmiR-155,let-7ctranscripts in progressing (n=20) comparing to regressing (n=28) disease as assessed by 2-year follow-up. Correlation network analysis revealed relationships between microRNAs, transcription factorT-bet, and deregulated cytokine/chemokine-receptor network in sarcoid BAL cells. Furthermore,T-betshowed more pronounced regulatory capability to sarcoidosis-associated cytokines/chemokines/receptors than miRNAs, which may function rather as “fine-tuners” of cytokine/chemokine expression. Our correlation network study implies contribution of both microRNAs and Th1-transcription factorT-betto the regulation of cytokine/chemokine-receptor network in BAL cells in sarcoidosis. Functional studies are needed to confirm biological relevance of the obtained relationships.
45
Jones, Iris K. A., Nicole N. Haese, Philippe Gatault, Zachary J. Streblow, Takeshi F. Andoh, Michael Denton, Cassilyn E. Streblow, et al. "Rat Cytomegalovirus Virion-Associated Proteins R131 and R129 Are Necessary for Infection of Macrophages and Dendritic Cells." Pathogens 9, no. 11 (November 19, 2020): 963. http://dx.doi.org/10.3390/pathogens9110963.
Full textAbstract:
Cytomegalovirus (CMV) establishes persistent, latent infection in hosts, causing diseases in immunocompromised patients, transplant recipients, and neonates. CMV infection modifies the host chemokine axis by modulating chemokine and chemokine receptor expression and by encoding putative chemokine and chemokine receptor homologues. The viral proteins have roles in cellular signaling, migration, and transformation, as well as viral dissemination, tropism, latency and reactivation. Herein, we review the contribution of CMV-encoded chemokines and chemokine receptors to these processes, and further elucidate the viral tropism role of rat CMV (RCMV) R129 and R131. These homologues of the human CMV (HCMV)-encoded chemokines UL128 and UL130 are of particular interest because of their dual role as chemokines and members of the pentameric entry complex, which is required for entry into cell types that are essential for viral transmission and dissemination. The contributions of UL128 and UL130 to acceleration of solid organ transplant chronic rejection are poorly understood, and are in need of an effective in vivo model system to elucidate the phenomenon. We demonstrated similar molecular entry requirements for R129 and R131 in the rat cells, as observed for HCMV, and provided evidence that R129 and R131 are part of the viral entry complex required for entry into macrophages, dendritic cells, and bone marrow cells.
46
Signoret, N., M. M. Rosenkilde, P. J. Klasse, T. W. Schwartz, M. H. Malim, J. A. Hoxie, and M. Marsh. "Differential regulation of CXCR4 and CCR5 endocytosis." Journal of Cell Science 111, no. 18 (September 15, 1998): 2819–30. http://dx.doi.org/10.1242/jcs.111.18.2819.
Full textAbstract:
The chemokine receptors CCR5 and CXCR4 are major co-receptors/receptors for the CD4-dependent and CD4-independent entry of human and simian immunodeficiency viruses. The chemokines that bind and activate these receptors can inhibit the entry of viruses that use the respective co-receptor molecules. Chemokine-induced co-receptor internalisation is a significant component of the mechanism through which chemokines inhibit virus entry. CXCR4 internalisation is induced by the CXCR4 ligand stromal cell derived factor-1 (SDF-1), phorbol esters and, in T cells, cellular activation. Here we show that CXCR4 endocytosis can be mediated through either one of two distinct internalisation signals. A COOH-terminal serine rich domain is required for ligand- but not phorbol ester- induced CXCR4 internalisation. However, a Ser/IleLeu motif, similar to that required for the endocytosis of CD4 and the T cell receptor/CD3 complex, is required for phorbol ester-induced, but not ligand-induced, CXCR4 endocytosis. By contrast, CCR5 internalisation is induced by the beta-chemokine RANTES but not by phorbol esters. CCR5 lacks the Ser/IleLeu sequence required for phorbol ester-induced uptake of CXCR4. Together these results indicate that distinct mechanisms can regulate CXCR4 and CCR5 endocytosis and trafficking.
47
Shi, Guixiu, Santiago Partida-Sánchez, Ravi S. Misra, Michael Tighe, Michael T. Borchers, James J. Lee, Melvin I. Simon, and Frances E. Lund. "Identification of an alternative Gαq-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes." Journal of Experimental Medicine 204, no. 11 (October 15, 2007): 2705–18. http://dx.doi.org/10.1084/jem.20071267.
Full textAbstract:
CD38 controls the chemotaxis of leukocytes to some, but not all, chemokines, suggesting that chemokine receptor signaling in leukocytes is more diverse than previously appreciated. To determine the basis for this signaling heterogeneity, we examined the chemokine receptors that signal in a CD38-dependent manner and identified a novel “alternative” chemokine receptor signaling pathway. Similar to the “classical” signaling pathway, the alternative chemokine receptor pathway is activated by Gαi2-containing Gi proteins. However, unlike the classical pathway, the alternative pathway is also dependent on the Gq class of G proteins. We show that Gαq-deficient neutrophils and dendritic cells (DCs) make defective calcium and chemotactic responses upon stimulation with N-formyl methionyl leucyl phenylalanine and CC chemokine ligand (CCL) 3 (neutrophils), or upon stimulation with CCL2, CCL19, CCL21, and CXC chemokine ligand (CXCL) 12 (DCs). In contrast, Gαq-deficient T cell responses to CXCL12 and CCL19 remain intact. Thus, the alternative chemokine receptor pathway controls the migration of only a subset of cells. Regardless, the novel alternative chemokine receptor signaling pathway appears to be critically important for the initiation of inflammatory responses, as Gαq is required for the migration of DCs from the skin to draining lymph nodes after fluorescein isothiocyanate sensitization and the emigration of monocytes from the bone marrow into inflamed skin after contact sensitization.
48
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.
Full textAbstract:
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.
49
Liao, Xiaofeng, Tharshikha Pirapakaran, and Xin M. Luo. "Chemokines and Chemokine Receptors in the Development of Lupus Nephritis." Mediators of Inflammation 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/6012715.
Full textAbstract:
Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN.
50
Proost, P., S. Struyf, and J. Van Damme. "Natural post-translational modifications of chemokines." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 997–1001. http://dx.doi.org/10.1042/bst0340997.
Full textAbstract:
Chemokines, adhesion molecules, cytokines and proteases regulate the extravasation of leucocytes during acute and chronic inflammation and leucocyte homing. Chemokines are produced after transcriptional activation by inflammatory mediators such as cytokines or microbial Toll-like receptor ligands and their effect depends on the expression of chemokine receptors on specific cell types. More and more evidence points towards a role for post-translational modifications in the fine-tuning of chemokine activity. Although both glycosylation and proteolytic processing of the C- and/or N-terminus of chemokines has been reported, mainly proteolytic processing of the N-terminus appears to affect the receptor specificity, chemotactic property and signalling potency of these low-molecular-mass proteins. N-terminal processing of chemokines by aminopeptidases or endoproteases may alter the receptor specificity and may result in up- or down-regulation of their chemotactic, antiviral or angiogenic activity.