Journal articles on the topic 'ACKR4'
To see the other types of publications on this topic, follow the link: ACKR4.
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 'ACKR4.'
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
Pacheco, Messias Oliveira, Fernanda Agostini Rocha, Thiago Pinheiro Arrais Aloia, and Luciana Cavalheiro Marti. "Evaluation of Atypical Chemokine Receptor Expression in T Cell Subsets." Cells 11, no. 24 (December 16, 2022): 4099. http://dx.doi.org/10.3390/cells11244099.
Full textAbstract:
Chemokines are molecules that pertain to a family of small cytokines and can generate cell chemotaxis through the interaction with their receptors. Chemokines can trigger signaling via conventional G-protein-coupled receptors or through atypical chemokine receptors. Currently, four atypical chemokine receptors have been are described (ACKR1, ACKR2, ACKR3 and ACKR4). ACKRs are expressed in various cells and tissues, including T lymphocytes. These receptors’ main function is related to the internalization and degradation of chemokines, as well as to the inflammation control. However, the expression of these receptors in human T lymphocytes is unclear in the literature. The objective of this study was to evaluate the expression of ACKRs in different subpopulations of T lymphocytes. For this, peripheral blood from healthy donors was used to analyze the expression of ACKR2, ACKR3 and ACKR4 by immunophenotyping CD4, CD8 T lymphocytes and, in their subsets, naive, transition and memory. Results obtained in this study demonstrated that ACKR2, ACKR3 and ACKR4 receptors were expressed by T lymphocytes subsets in different proportions. These receptors are highly expressed in the cytoplasmic milieu of all subsets of T lymphocytes, therefore suggesting that their expression in plasma membrane is regulated after transcription, and it must be dependent on a stimulus, which was not identified in our study. Thus, regarding ACKRs function as scavenger receptors, at least for the ACKR3, this function does not impair the chemotaxis exert for their ligand compared to the typical counterpart receptor.
2
Pan, Li, Jianliang Lv, Zhongwang Zhang, and Yongguang Zhang. "Adaptation and Constraint in the Atypical Chemokine Receptor Family in Mammals." BioMed Research International 2018 (September 24, 2018): 1–9. http://dx.doi.org/10.1155/2018/9065181.
Full textAbstract:
Atypical chemokine receptors (ACKRs) are a subclass of G protein-coupled receptors characterized by promiscuity of ligand binding and an obvious inability to signal after ligand binding. Although some discoveries regarding this family in Homo sapiens and other species have been reported in some studies, the evolution and function of multiple ACKR in mammals have not yet been clearly understood. We performed an evolutionary analysis of ACKR genes (ACKR1, ACKR2, ACKR3, and ACKR4) in mammals. Ninety-two full-length ACKR genes from 27 mammal species were retrieved from the Genbank and Ensemble databases. Phylogenetic analysis showed that there were four well-conserved subfamilies in mammals. Synteny analysis revealed that ACKR genes formed conserved linkage groups with their adjacent genes across mammalian species, facilitating the identification of ACKRs in as yet unannotated genome datasets. Analysis of the site-specific profiles established by posterior probability revealed the positive-selection sites to be distributed mainly in the ligand binding region of ACKR1. This study highlights the molecular evolution of the ACKR gene family in mammals and identifies the critical amino acid residues likely to be relevant to ligand binding. Further experimental verification of these findings may provide valuable information regarding the ACKR’s biochemical and physiological functions.
3
Lewandowska, Paulina, Jaroslaw Wierzbicki, Marek Zawadzki, Anil Agrawal, and Małgorzata Krzystek-Korpacka. "Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings." Biomolecules 11, no. 1 (December 23, 2020): 8. http://dx.doi.org/10.3390/biom11010008.
Full textAbstract:
Facilitating resolution of inflammation using atypical chemokine receptors (ACKR) as an anticancer strategy is considered but requires a deeper understanding of receptor role in carcinogenesis. We aimed at transcriptional analysis (RTqPCR) of ACKR2 and ACKR4 expression in colorectal adenoma-adenocarcinoma sequence in paired normal-neoplastic tissues from 96 polyps and 51 cancers. On average, ACKR2 was downregulated in neoplastic as compared to non-affected tissue in polyp (by 2.7-fold) and cancer (by 3.1-fold) patients. The maximal downregulation (by 8.2-fold) was observed in adenomas with the highest potential for malignancy and was gradually lessening through cancer stages I-IV, owing to increased receptor expression in tumors. On average, ACKR4 was significantly downregulated solely in adenocarcinomas (by 1.5-fold), less so in patients with lymph node metastasis, owing to a gradual decrease in ACKR4 expression among N0-N1-N2 cancers in non-affected tissue without changes in tumors. In adenomas, ACKR4 downregulation in neoplastic tissue increased with increasing potential for malignancy and contribution of villous growth pattern. ACKR4 expression increased in non-affected tissue with a concomitant decrease in pathological mucosa. In conclusion, the changes in ACKRs expression occur already in precancerous colorectal lesions, culminating in the adenomas with the highest potential for malignancy. Therefore, chemoprevention by manipulating ACKRs’ expression is worth exploration.
4
Wangmo, Dechen, Prem K. Premsrirut, Ce Yuan, William S. Morris, Xianda Zhao, and Subbaya Subramanian. "ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming." Cancers 13, no. 19 (October 7, 2021): 5021. http://dx.doi.org/10.3390/cancers13195021.
Full textAbstract:
Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregulation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.
5
Bastow, Cameron R., Mark D. Bunting, Ervin E. Kara, Duncan R. McKenzie, Adriana Caon, Sapna Devi, Lynn Tolley, et al. "Scavenging of soluble and immobilized CCL21 by ACKR4 regulates peripheral dendritic cell emigration." Proceedings of the National Academy of Sciences 118, no. 17 (April 19, 2021): e2025763118. http://dx.doi.org/10.1073/pnas.2025763118.
Full textAbstract:
Leukocyte homing driven by the chemokine CCL21 is pivotal for adaptive immunity because it controls dendritic cell (DC) and T cell migration through CCR7. ACKR4 scavenges CCL21 and has been shown to play an essential role in DC trafficking at the steady state and during immune responses to tumors and cutaneous inflammation. However, the mechanism by which ACKR4 regulates peripheral DC migration is unknown, and the extent to which it regulates CCL21 in steady-state skin and lymph nodes (LNs) is contested. Specifically, our previous findings that CCL21 levels are increased in LNs of ACKR4-deficient mice [I. Comerford et al., Blood 116, 4130–4140 (2010)] were refuted [M. H. Ulvmar et al., Nat. Immunol. 15, 623–630 (2014)], and no differences in CCL21 levels in steady-state skin of ACKR4-deficient mice were reported despite compromised CCR7-dependent DC egress in these animals [S. A. Bryce et al., J. Immunol. 196, 3341–3353 (2016)]. Here, we resolve these issues and reveal that two forms of CCL21, full-length immobilized and cleaved soluble CCL21, exist in steady-state barrier tissues, and both are regulated by ACKR4. Without ACKR4, extracellular CCL21 gradients in barrier sites are saturated and nonfunctional, DCs cannot home directly to lymphatic vessels, and excess soluble CCL21 from peripheral tissues pollutes downstream LNs. The results identify the mechanism by which ACKR4 controls DC migration in barrier tissues and reveal a complex mode of CCL21 regulation in vivo, which enhances understanding of functional chemokine gradient formation.
6
Kara, Ervin E., Cameron R. Bastow, Duncan R. McKenzie, Carly E. Gregor, Kevin A. Fenix, Rachelle Babb, Todd S. Norton, et al. "Atypical chemokine receptor 4 shapes activated B cell fate." Journal of Experimental Medicine 215, no. 3 (January 31, 2018): 801–13. http://dx.doi.org/10.1084/jem.20171067.
Full textAbstract:
Activated B cells can initially differentiate into three functionally distinct fates—early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells—by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell–intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.
7
Bryce, Steven, Darren Asquith, Shannon Bromley, Andrew Luster, Gerard Graham, and Robert Nibbs. "The atypical chemokine receptor ACKR4 facilitates dendritic cell migration during inflammation by scavenging CCL19 (CCR3P.205)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 49.6. http://dx.doi.org/10.4049/jimmunol.194.supp.49.6.
Full textAbstract:
Abstract The migration of dendritic cells from tissues to draining lymph nodes is a critical step in the induction of peripheral tolerance and the initiation of adaptive immune responses. This is dependent on CCR7 expression by dendritic cells. In response to the chemokine CCL21, CCR7 directs dendritic cells into lymphatic vessels in the tissue, and permits their transit from the subcapsular sinus into the lymph node parenchyma. The CCR7 ligands CCL19 and CCL21 also bind ACKR4, an atypical chemokine receptor expressed by keratinocytes in the skin and lymphatic endothelial cells lining the subcapsular sinus. In mice, ACKR4 controls interfollicular CCL21 gradients, and enhances dendritic cell entry into the lymph node parenchyma from the subcapsular sinus. Here we report that Ackr4 deficiency disrupts CCR7-dependent dendritic cell arrival at skin-draining lymph nodes during cutaneous inflammation. We show that this, at least in part, is due to the defective departure of dendritic cells from inflamed skin, and is accompanied by dysregulation of bioavailable CCL19 and CCL21 in the skin. Strikingly, genetic deletion of CCL19 completely rescues the defective inflammation-driven trafficking of dendritic cells caused by Ackr4 deficiency. Thus, by regulating CCL19, ACKR4 helps maintain CCR7-dependent dendritic cell departure from inflamed tissues.
8
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.
Full textAbstract:
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.
9
Eckert, Nadine, Kathrin Werth, Stefanie Willenzon, Likai Tan, and Reinhold Förster. "B cell hyperactivation in an Ackr4 ‐deficient mouse strain is not caused by lack of ACKR4 expression." Journal of Leukocyte Biology 107, no. 6 (December 16, 2019): 1155–66. http://dx.doi.org/10.1002/jlb.2ma1119-300r.
Full text
10
Mohammed, Mostafa M., Olfat Shaker, Maggie M. Ramzy, Shereen S. Gaber, Heba S. Kamel, and Mohamed F. Abed EL Baky. "The relation between ACKR4 and CCR7 genes expression and breast cancer metastasis." Life Sciences 279 (August 2021): 119691. http://dx.doi.org/10.1016/j.lfs.2021.119691.
Full text
11
Gutjahr, Julia C., Kyler S. Crawford, Davin R. Jensen, Prachi Naik, Francis C. Peterson, Guerric P. B. Samson, Daniel F. Legler, et al. "The dimeric form of CXCL12 binds to atypical chemokine receptor 1." Science Signaling 14, no. 696 (August 17, 2021): eabc9012. http://dx.doi.org/10.1126/scisignal.abc9012.
Full textAbstract:
The pleiotropic chemokine CXCL12 is involved in diverse physiological and pathophysiological processes, including embryogenesis, hematopoiesis, leukocyte migration, and tumor metastasis. It is known to engage the classical receptor CXCR4 and the atypical receptor ACKR3. Differential receptor engagement can transduce distinct cellular signals and effects as well as alter the amount of free, extracellular chemokine. CXCR4 binds both monomeric and the more commonly found dimeric forms of CXCL12, whereas ACKR3 binds monomeric forms. Here, we found that CXCL12 also bound to the atypical receptor ACKR1 (previously known as Duffy antigen/receptor for chemokines or DARC). In vitro nuclear magnetic resonance spectroscopy and isothermal titration calorimetry revealed that dimeric CXCL12 bound to the extracellular N terminus of ACKR1 with low nanomolar affinity, whereas the binding affinity of monomeric CXCL12 was orders of magnitude lower. In transfected MDCK cells and primary human Duffy-positive erythrocytes, a dimeric, but not a monomeric, construct of CXCL12 efficiently bound to and internalized with ACKR1. This interaction between CXCL12 and ACKR1 provides another layer of regulation of the multiple biological functions of CXCL12. The findings also raise the possibility that ACKR1 can bind other dimeric chemokines, thus potentially further expanding the role of ACKR1 in chemokine retention and presentation.
12
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.
13
Zhang, Min, Min Zhang, Ting Zhou, Meilin Liu, Ni Xia, Muyang Gu, Tingting Tang, et al. "Inhibition of fibroblast IL-6 production by ACKR4 deletion alleviates cardiac remodeling after myocardial infarction." Biochemical and Biophysical Research Communications 547 (April 2021): 139–47. http://dx.doi.org/10.1016/j.bbrc.2021.02.013.
Full text
14
Albee, Lauren J., Heather M. LaPorte, Xianlong Gao, Jonathan M. Eby, You-Hong Cheng, Amanda M. Nevins, Brian F. Volkman, Vadim Gaponenko, and Matthias Majetschak. "Identification and functional characterization of arginine vasopressin receptor 1A : atypical chemokine receptor 3 heteromers in vascular smooth muscle." Open Biology 8, no. 1 (January 2018): 170207. http://dx.doi.org/10.1098/rsob.170207.
Full textAbstract:
Recent observations suggest that atypical chemokine receptor (ACKR)3 and chemokine (C-X-C motif) receptor (CXCR)4 regulate human vascular smooth muscle function through hetero-oligomerization with α 1 -adrenoceptors. Here, we show that ACKR3 also regulates arginine vasopressin receptor (AVPR)1A. We observed that ACKR3 agonists inhibit arginine vasopressin (aVP)-induced inositol trisphosphate (IP 3 ) production in human vascular smooth muscle cells (hVSMCs) and antagonize aVP-mediated constriction of isolated arteries. Proximity ligation assays, co-immunoprecipitation and bioluminescence resonance energy transfer experiments suggested that recombinant and endogenous ACKR3 and AVPR1A interact on the cell surface. Interference with ACKR3 : AVPR1A heteromerization using siRNA and peptide analogues of transmembrane domains of ACKR3 abolished aVP-induced IP 3 production. aVP stimulation resulted in β-arrestin 2 recruitment to AVPR1A and ACKR3. While ACKR3 activation failed to cross-recruit β-arrestin 2 to AVPR1A, the presence of ACKR3 reduced the efficacy of aVP-induced β-arrestin 2 recruitment to AVPR1A. AVPR1A and ACKR3 co-internalized upon agonist stimulation in hVSMC. These data suggest that AVPR1A : ACKR3 heteromers are constitutively expressed in hVSMC, provide insights into molecular events at the heteromeric receptor complex, and offer a mechanistic basis for interactions between the innate immune and vasoactive neurohormonal systems. Our findings suggest that ACKR3 is a regulator of vascular smooth muscle function and a possible drug target in diseases associated with impaired vascular reactivity.
15
Russo, Remo C., Benedetta Savino, Massimiliano Mirolo, Chiara Buracchi, Giovanni Germano, Achille Anselmo, Luca Zammataro, et al. "The atypical chemokine receptor ACKR2 drives pulmonary fibrosis by tuning influx of CCR2+ and CCR5+ IFNγ-producing γδT cells in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 314, no. 6 (June 1, 2018): L1010—L1025. http://dx.doi.org/10.1152/ajplung.00233.2017.
Full textAbstract:
Chemokines coordinate lung inflammation and fibrosis by acting on chemokine receptors expressed on leukocytes and other cell types. Atypical chemokine receptors (ACKRs) bind, internalize, and degrade chemokines, tuning homeostasis and immune responses. ACKR2 recognizes and decreases the levels of inflammatory CC chemokines. The role of ACKR2 in fibrogenesis is unknown. The purpose of the study was to investigate the role of ACKR2 in the context of pulmonary fibrosis. The effects of ACKR2 expression and deficiency during inflammation and fibrosis were analyzed using a bleomycin-model of fibrosis, ACKR2-deficient mice, bone marrow chimeras, and antibody-mediated leukocyte depletion. ACKR2 was upregulated acutely in response to bleomycin and normalized over time. ACKR2−/− mice showed reduced lethality and lung fibrosis. Bone marrow chimeras showed that lethality and fibrosis depended on ACKR2 expression in pulmonary resident (nonhematopoietic) cells but not on leukocytes. ACKR2−/− mice exhibited decreased expression of tissue-remodeling genes, reduced leukocyte influx, pulmonary injury, and dysfunction. ACKR2−/− mice had early increased levels of CCL5, CCL12, CCL17, and IFNγ and an increased number of CCR2+ and CCR5+ IFNγ-producing γδT cells in the airways counterbalanced by low Th17-lymphocyte influx. There was reduced accumulation of IFNγ-producing γδT cells in CCR2−/− and CCR5−/− mice. Moreover, depletion of γδT cells worsened the clinical symptoms induced by bleomycin and reversed the phenotype of ACKR2−/− mice exposed to bleomycin. ACKR2 controls the CC chemokine expression that drives the influx of CCR2+ and CCR5+ IFNγ-producing γδT cells, tuning the Th17 response that mediated pulmonary fibrosis triggered by bleomycin instillation.
16
Werth, Kathrin, Elin Hub, Julia Christine Gutjahr, Berislav Bosjnak, Xiang Zheng, Anja Bubke, Stefan Russo, Antal Rot, and Reinhold Förster. "Expression of ACKR4 demarcates the “peri-marginal sinus,” a specialized vascular compartment of the splenic red pulp." Cell Reports 36, no. 2 (July 2021): 109346. http://dx.doi.org/10.1016/j.celrep.2021.109346.
Full text
17
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.
18
Parsi, Bahareh, Abolghasem Esmaeili, Mohammad Hashemi, and Mohaddeseh Behjati. "Transient expression of recombinant ACKR4 (CCRL1) gene, an atypical chemokine receptor in human embryonic kidney (HEK 293) cells." Molecular Biology Reports 43, no. 7 (May 11, 2016): 583–89. http://dx.doi.org/10.1007/s11033-016-3995-x.
Full text
19
Sun, Yiping, Xueqing Hu, Kui Zhang, Man Rao, Pengbin Yin, and Ran Dong. "A Single-Cell Survey of Cellular Heterogeneity in Human Great Saphenous Veins." Cells 11, no. 17 (August 31, 2022): 2711. http://dx.doi.org/10.3390/cells11172711.
Full textAbstract:
Background: The great saphenous vein (GSV) is the most commonly used conduit for coronary arterial bypass graft. However, the status of the GSV, including metabolic dysfunction such as diabetes mellitus (DM) complication, is strongly associated with vein graft failure (VGF). To date, the molecular mechanism underlying VGF remains elusive. Detailed characterization of the cellular components and corresponding expression regulation in GSVs would be of great importance for clinical decision making to reduce VGF. Methods: To this end, we performed single-cell RNA sequencing to delineate cellular heterogeneity in three human GSV samples. Results: Scrutinization of cellular composition and expression revealed cell diversity in human GSVs, particularly endothelial cells (ECs). Our results unraveled that functional adaptation drove great expression differences between venous ECs and valvular ECs. For instance, cell surface receptor ACKR1 demarcated venous Ecs, whereas ACRK3/ACKR4 were exclusively expressed by valvular ECs. Differential gene expression analysis suggested that genes highly expressed in venous ECs were mainly involved in vasculature development and regulation of leukocyte adhesion, whereas valvular ECs have more pronounced expression of genes participating in extracellular matrix organization, ossification and platelet degranulation. Of note, pseudo-time trajectory analysis provided in silico evidence indicating that venous ECs, valvular ECs and lymphatic vessels were developmentally connected. Further, valvular ECs might be an importance source for lymphatic vessel differentiation in adults. Additionally, we found a venous EC subset highly expressing IL6, which might be associated with undesirable prognosis. Meanwhile, we identified a population of ANGPTL7+ fibroblasts (FBs), which may be profibrotic and involved in insulin resistance in human GSVs. Additionally, our data suggest that immune cells only accounted for a small fraction, most of which were macrophages. By assessing the intertwined remodeling in metabolic dysfunction that potentially increases the gene expression regulatory network in mural cells and leukocytes, we found that transcription factor KLF9 likely operated a proinflammatory program, inducing the transcription of metallothionein proteins in two mural cell subsets and proinflammatory immune cells. Lastly, cellular communication analysis revealed that proinflammatory signaling, including TRAIL, PVR, CSF and GDF, were uniquely activated in patients with metabolic dysfunction. Conclusions: Our results identified critical cell-specific responses and cellular interactions in GSVs. Beyond serving as a repertoire, this work illustrates multifactorial likelihood of VGF.
20
Gencer, Selin, Emiel van der Vorst, Maria Aslani, Christian Weber, Yvonne Döring, and Johan Duchene. "Atypical Chemokine Receptors in Cardiovascular Disease." Thrombosis and Haemostasis 119, no. 04 (February 4, 2019): 534–41. http://dx.doi.org/10.1055/s-0038-1676988.
Full textAbstract:
AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.
21
Bryce, Steven A., Ruairi A. M. Wilson, Eleanor M. Tiplady, Darren L. Asquith, Shannon K. Bromley, Andrew D. Luster, Gerard J. Graham, and Robert J. B. Nibbs. "ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes." Journal of Immunology 196, no. 8 (March 14, 2016): 3341–53. http://dx.doi.org/10.4049/jimmunol.1501542.
Full text
22
Kleist, Andrew B., Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie I. Anderson, et al. "Conformational selection guides β-arrestin recruitment at a biased G protein–coupled receptor." Science 377, no. 6602 (July 8, 2022): 222–28. http://dx.doi.org/10.1126/science.abj4922.
Full textAbstract:
G protein–coupled receptors (GPCRs) recruit β-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage β-arrestins but not G proteins, making them a model system for investigating the structural basis of β-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13 CH 3 -ε–methionine–labeled ACKR3, revealing that β-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular β-arrestin–coupling region. NMR studies of ACKR3 mutants defective in β-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides β-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.
23
Friess, Mona C., Ioannis Kritikos, Philipp Schineis, Jessica Danielly Medina-Sanchez, Anastasia-Olga Gkountidi, Angela Vallone, Elena C. Sigmund, et al. "Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics." Cell Reports 38, no. 5 (February 2022): 110334. http://dx.doi.org/10.1016/j.celrep.2022.110334.
Full text
24
Lucas, Beth, Andrea J. White, Maria H. Ulvmar, Robert J. B. Nibbs, Katarzyna M. Sitnik, William W. Agace, William E. Jenkinson, Graham Anderson, and Antal Rot. "CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice." European Journal of Immunology 45, no. 2 (January 16, 2015): 574–83. http://dx.doi.org/10.1002/eji.201445015.
Full text
25
Mackie, Duncan I., Natalie R. Nielsen, Matthew Harris, Smriti Singh, Reema B. Davis, Danica Dy, Graham Ladds, and Kathleen M. Caron. "RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis." Proceedings of the National Academy of Sciences 116, no. 48 (November 11, 2019): 24093–99. http://dx.doi.org/10.1073/pnas.1905561116.
Full textAbstract:
Receptor-activity–modifying proteins (RAMPs) are single transmembrane-spanning proteins which serve as molecular chaperones and allosteric modulators of G-protein–coupled receptors (GPCRs) and their signaling pathways. Although RAMPs have been previously studied in the context of their effects on Family B GPCRs, the coevolution of RAMPs with many GPCR families suggests an expanded repertoire of potential interactions. Using bioluminescence resonance energy transfer-based and cell-surface expression approaches, we comprehensively screen for RAMP interactions within the chemokine receptor family and identify robust interactions between RAMPs and nearly all chemokine receptors. Most notably, we identify robust RAMP interaction with atypical chemokine receptors (ACKRs), which function to establish chemotactic gradients for directed cell migration. Specifically, RAMP3 association with atypical chemokine receptor 3 (ACKR3) diminishes adrenomedullin (AM) ligand availability without changing G-protein coupling. Instead, RAMP3 is required for the rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following either AM or SDF-1/CXCL12 binding, thereby enabling formation of dynamic spatiotemporal chemotactic gradients. Consequently, genetic deletion of either ACKR3 or RAMP3 in mice abolishes directed cell migration of retinal angiogenesis. Thus, RAMP association with chemokine receptor family members represents a molecular interaction to control receptor signaling and trafficking properties.
26
Thomson, Carolyn A., Serge A. van de Pavert, Michelle Stakenborg, Evelien Labeeuw, Gianluca Matteoli, Allan McI Mowat, and Robert J. B. Nibbs. "Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel Population of Intestinal Submucosal Fibroblasts That Preferentially Expresses Endothelial Cell Regulators." Journal of Immunology 201, no. 1 (May 14, 2018): 215–29. http://dx.doi.org/10.4049/jimmunol.1700967.
Full text
27
Jafarnejad, Mohammad, David C. Zawieja, Bindi S. Brook, Robert J. B. Nibbs, and James E. Moore. "A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4." Journal of Immunology 199, no. 7 (August 14, 2017): 2291–304. http://dx.doi.org/10.4049/jimmunol.1700377.
Full text
28
Guo, Rui, Guangwei Ma, Xiaofei Zhai, Haitao Shi, and Jichao Wang. "Comparison of the Single-Cell Immune Landscape of Testudines from Different Habitats." Cells 11, no. 24 (December 12, 2022): 4023. http://dx.doi.org/10.3390/cells11244023.
Full textAbstract:
Testudines, also known as living fossils, have evolved diversely and comprise many species that occupy a variety of ecological niches. However, the immune adaptation of testudines to the different ecological niches remains poorly understood. This study compared the composition, function, and differentiation trajectories of peripheral immune cells in testudines (Chelonia mydas, Trachemys scripta elegans, Chelonoidis carbonaria, and Pelodiscus sinensis) from different habitats using the single-cell RNA sequencing (scRNA-seq) technique. The results showed that T. scripta elegans, which inhabits freshwater and brackish environments, had the most complex composition of peripheral immune cells, with 11 distinct immune cell subsets identified in total. The sea turtle C. mydas, had the simplest composition of peripheral immune cells, with only 5 distinct immune cell clusters. Surprisingly, neither basophils were found in C. mydas nor T cells in C. carbonaria. Basophil subsets in peripheral blood were identified for the first time; two basophil subtypes (GATA2-high-basophils and GATA2-low-basophils) were observed in the peripheral blood of T. scripta elegans. In addition, ACKR4 cells, CD4 T cells, CD7 T cells, serotriflin cells, and ficolin cells were specifically identified in the peripheral blood of T. scripta elegans. Furthermore, LY6G6C cells, SPC24 cells, and NKT cells were specifically observed in C. carbonaria. Moreover, there were differences in the functional status and developmental trajectory of peripheral immune cells among the testudine species. The identification of specific features of peripheral immune cells in testudines from different habitats may enable elucidation of the adaptation mechanism of testudines to various ecological niches.
29
Caliskan, Aylin, Samantha A. W. Crouch, Sara Giddins, Thomas Dandekar, and Seema Dangwal. "Progeria and Aging—Omics Based Comparative Analysis." Biomedicines 10, no. 10 (September 29, 2022): 2440. http://dx.doi.org/10.3390/biomedicines10102440.
Full textAbstract:
Since ancient times aging has also been regarded as a disease, and humankind has always strived to extend the natural lifespan. Analyzing the genes involved in aging and disease allows for finding important indicators and biological markers for pathologies and possible therapeutic targets. An example of the use of omics technologies is the research regarding aging and the rare and fatal premature aging syndrome progeria (Hutchinson-Gilford progeria syndrome, HGPS). In our study, we focused on the in silico analysis of differentially expressed genes (DEGs) in progeria and aging, using a publicly available RNA-Seq dataset (GEO dataset GSE113957) and a variety of bioinformatics tools. Despite the GSE113957 RNA-Seq dataset being well-known and frequently analyzed, the RNA-Seq data shared by Fleischer et al. is far from exhausted and reusing and repurposing the data still reveals new insights. By analyzing the literature citing the use of the dataset and subsequently conducting a comparative analysis comparing the RNA-Seq data analyses of different subsets of the dataset (healthy children, nonagenarians and progeria patients), we identified several genes involved in both natural aging and progeria (KRT8, KRT18, ACKR4, CCL2, UCP2, ADAMTS15, ACTN4P1, WNT16, IGFBP2). Further analyzing these genes and the pathways involved indicated their possible roles in aging, suggesting the need for further in vitro and in vivo research. In this paper, we (1) compare “normal aging” (nonagenarians vs. healthy children) and progeria (HGPS patients vs. healthy children), (2) enlist genes possibly involved in both the natural aging process and progeria, including the first mention of IGFBP2 in progeria, (3) predict miRNAs and interactomes for WNT16 (hsa-mir-181a-5p), UCP2 (hsa-mir-26a-5p and hsa-mir-124-3p), and IGFBP2 (hsa-mir-124-3p, hsa-mir-126-3p, and hsa-mir-27b-3p), (4) demonstrate the compatibility of well-established R packages for RNA-Seq analysis for researchers interested but not yet familiar with this kind of analysis, and (5) present comparative proteomics analyses to show an association between our RNA-Seq data analyses and corresponding changes in protein expression.
30
Mohammed, Faruk, Melissa B. Davis, Clayton C. Yates, and Halimatu Sadiya Musa. "Abstract C050: The role of PD-L1, ACKR/DARC, Livin and Annexin A5 in malignant tumours of the bone, prostate, breast, eye/orbit, nasopharynx, and metastatic carcinomas to the brain, neck and lymph node among West Africans in Zaria, Nigeria." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C050. http://dx.doi.org/10.1158/1538-7755.disp22-c050.
Full textAbstract:
Abstract Cancer ranks as a leading cause of death and an important barrier to increasing life expectancy worldwide. Globally, there are estimated 19.3 million new cancer cases and about 10 million cancer mortality in 2020. Should current cancer trends continue, Africa’s cancer burden is projected to reach an alarming 1.4 million new cases and 1 million deaths by 2030. Thus, racial/ethnic disparities in cancer morbidity and mortality continue to widen globally but molecular biology and genomic studies rarely interrogate cancer in diverse disadvantaged populations. Effective control of tumour growth in cancer microenvironment is facilitated by cellular interaction between innate and adaptive immune cells. The programmed death ligand-1 (PD-L1), an immune checkpoint expressed on tumour cells, facilitates the escape of immunosurveillance in cancer by interacting with programmed death-1 (PD-1) to initiate apoptosis of the immune cells. The interaction between these immune cells may be mediated by atypical chemokine receptor 1 (ACKR1)/Duffy antigen receptor for chemokines (DARC) towards activation of tumour-specific immune response by chemoattraction of leukocytes to the inflammatory sites. Livin/BIRC7 protein overexpression is a key component of evasion of apoptosis in cancer cells. Interestingly, Annexin A5, an important member of Annexin family of proteins with high affinity to phosphatidylserine, has been reported to serve as an important component of apoptosis by stimulating immunogenicity of tumor cells. In this pilot study, we report using immunohistochemistry, RNA-seq and whole exome sequencing the expression pattern and functional significance of PD-L1, ACKR/DARC, Livin/BIRC7 and Annexin A5 in malignant tumours of the bone, prostate, breast, eye/orbit, nasopharynx, and metastatic carcinomas to the brain, neck and lymph node among West Africans in Zaria, Nigeria. In osteosarcoma and osteogenic sarcoma of the bone, we observed negative expression of ACKR/DARC and PD-L1, and overexpression of Livin and Annexin A5 proteins. However, a mucoepidermoid carcinoma of the index finger shows strong expression of ACKR/DARC, PD-L1 and Annexin A5 with poor expression of Livin protein. The results also show negative expression of ACKR/DARC, PD-L1 and Livin proteins from retinoblastoma, nasopharyngeal carcinoma, metastatic adenosquamous carcinoma to the parietal lobe of the brain, Metastatic squamous neck cancer, metastatic carcinoma of the lymph nodes and invasive breast carcinoma no special type (NST) grade 3. Prostate adenocarcinomas with Gleason grade 9 show negative expression of ACKR/DARC and PD-L1 proteins. All the tumours studied are strongly positive for Annexin A5 expression. The diverse expression pattern of ACKR/DARC, PD-L1, Livin and Annexin A5 in malignant tumours of the bone, retina, nasopharynx, breast, prostate and metastatic carcinomas to the brain, neck and lymph may be of significant importance in tumour behaviour and prognosis. Citation Format: Faruk Mohammed, Melissa B. Davis, Clayton C. Yates, Halimatu Sadiya Musa. The role of PD-L1, ACKR/DARC, Livin and Annexin A5 in malignant tumours of the bone, prostate, breast, eye/orbit, nasopharynx, and metastatic carcinomas to the brain, neck and lymph node among West Africans in Zaria, Nigeria [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C050.
31
Sigmund, Elena C., Lilian Baur, Philipp Schineis, Jorge Arasa, Victor Collado-Diaz, Martina Vranova, Rolf A. K. Stahl, Marcus Thelen, and Cornelia Halin. "Lymphatic endothelial-cell expressed ACKR3 is dispensable for postnatal lymphangiogenesis and lymphatic drainage function in mice." PLOS ONE 16, no. 4 (April 15, 2021): e0249068. http://dx.doi.org/10.1371/journal.pone.0249068.
Full textAbstract:
Atypical chemokine receptor ACKR3 (formerly CXCR7) is a scavenging receptor that has recently been implicated in murine lymphatic development. Specifically, ACKR3-deficiency was shown to result in lymphatic hyperplasia and lymphedema, in addition to cardiac hyperplasia and cardiac valve defects leading to embryonic lethality. The lymphatic phenotype was attributed to a lymphatic endothelial cell (LEC)-intrinsic scavenging function of ACKR3 for the vascular peptide hormone adrenomedullin (AM), which is also important during postnatal lymphangiogenesis. In this study, we investigated the expression of ACKR3 in the lymphatic vasculature of adult mice and its function in postnatal lymphatic development and function. We show that ACKR3 is widely expressed in mature lymphatics and that it exerts chemokine-scavenging activity in cultured murine skin-derived LECs. To investigate the role of LEC-expressed ACKR3 in postnatal lymphangiogenesis and function during adulthood, we generated and validated a lymphatic-specific, inducible ACKR3 knockout mouse. Surprisingly, in contrast to the reported involvement of ACKR3 in lymphatic development, our analyses revealed no contribution of LEC-expressed ACKR3 to postnatal lymphangiogenesis, lymphatic morphology and drainage function.
32
Zheng, Shirong, Susan Coventry, Lu Cai, David W. Powell, Venkatakrishna R. Jala, Bodduluri Haribabu, and Paul N. Epstein. "Renal Protection by Genetic Deletion of the Atypical Chemokine Receptor ACKR2 in Diabetic OVE Mice." Journal of Diabetes Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/5362506.
Full textAbstract:
In diabetic nephropathy (DN) proinflammatory chemokines and leukocyte infiltration correlate with tubulointerstitial injury and declining renal function. The atypical chemokine receptor ACKR2 is a chemokine scavenger receptor which binds and sequesters many inflammatory CC chemokines but does not transduce typical G-protein mediated signaling events. ACKR2 is known to regulate diverse inflammatory diseases but its role in DN has not been tested. In this study, we utilized ACKR2−/−mice to test whether ACKR2 elimination alters progression of diabetic kidney disease. Elimination of ACKR2 greatly reduced DN in OVE26 mice, an established DN model. Albuminuria was significantly lower at 2, 4, and 6 months of age. ACKR2 deletion did not affect diabetic blood glucose levels but significantly decreased parameters of renal inflammation including leukocyte infiltration and fibrosis. Activation of pathways that increase inflammatory gene expression was attenuated. Human biopsies stained with ACKR2 antibody revealed increased staining in diabetic kidney, especially in some tubule and interstitial cells. The results demonstrate a significant interaction between diabetes and ACKR2 protein in the kidney. Unexpectedly, ACKR2 deletion reduced renal inflammation in diabetes and the ultimate response was a high degree of protection from diabetic nephropathy.
33
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.
34
Martini, Rachel, Petros Nikolinakos, Jamie Hodgson, Brittany Jenkins, and Melissa Davis. "The role of atypical chemokine receptor-1 in breast cancer immune response." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23072-e23072. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23072.
Full textAbstract:
e23072 Background: Interactions between chemokines and their receptors can regulate anti-tumor response by influencing the migration of immune cells. Atypical Chemokine Receptor 1 (ACKR1/DARC), a genetically diverse transmembrane GPCR, acts as a decoy receptor for a variety of CXC and CC chemokines, including those with pro-malignant and pro-inflammatory effects, such as CCL2 and CXCL8 . The purpose of this study is to determine if the migration of tumor-associated immune cells is unique based on epithelial ACKR1 expression on breast cancer cells, and if this association is correlated to an increase in pro-malignant chemokines, survival, or race. Methods: Immunohistochemistry techniques were used to determine expression of ACKR1 on primary breast tumors, along with T-cells, B-cells, dendritic cells, and macrophages. Concentrations of pro-inflammatory chemokines in circulation were determined using a Luminex-based immunoassay. In silco analyses were performed to determine associations between ACKR1 tumor status, race, and survival. Finally, using human breast cancer cell lines and immunofluorescence techniques, co-localization between ACKR1 and pro-inflammatory chemokines was investigated. Results: Results from these tests indicate that there is differential infiltration of immune cell types in tumors expressing ACKR1, , which were not detected in ACKR1 negative tumors. Significantly increased circulating CCL2 and CXCL8 chemokine levels we also determined to be positively correlated with ACKR1 expression in primary breast tumors. Survival analyses showed a significantly increased relapse free survival in patients having tumors with high ACKR1 expression, while investigations into racial differences revealed a significant race effect, with Caucasians having higher ACKR1 levels on their tumors than African-Americans. Finally, co-localization between ACKR1 with CCL2 and CXCL8 is observed in cultured human breast cancer cells. Conclusions: tumors positively expressing ACKR1 to have a more favorable prognosis suggest that a role of ACKR1 on breast tumor cells is to sequester pro-inflammatory chemokines in the tumor microenvironment, recruiting a distinct subset of tumor-associated immune cells.
35
Gencer, Selin, Yvonne Döring, Yvonne Jansen, Soyolmaa Bayasgalan, Olga Schengel, Madeleine Müller, Linsey J. F. Peters, Christian Weber, and Emiel P. C. van der Vorst. "Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue." Biomedicines 9, no. 4 (April 6, 2021): 394. http://dx.doi.org/10.3390/biomedicines9040394.
Full textAbstract:
Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. Although these findings point towards a role of ACKR3 in the regulation of lipid levels, the role of adipocyte-specific ACKR3 has not yet been studied exclusively in this context. In this study, we established adipocyte- and hepatocyte-specific knockouts of Ackr3 in ApoE-deficient mice in order to determine its impact on lipid levels under hyperlipidemic conditions. We show for the first time that adipocyte-specific deletion of Ackr3 results in reduced AT triglyceride and cholesterol content in ApoE-deficient mice, which coincides with increased peroxisome proliferator-activated receptor-γ (PPAR-γ) and increased Angptl4 expression. The role of adipocyte ACKR3 in lipid handling seems to be tissue-specific as hepatocyte ACKR3 deficiency did not demonstrate comparable effects. In summary, adipocyte-specific ACKR3 seems to regulate AT lipid levels in hyperlipidemic Apoe−/− mice, which may therefore be a significant determinant of AT health. Further studies are needed to explore the potential systemic or metabolic effects that adipocyte ACKR3 might have in associated disease models.
36
Vacchini, Alessandro, Cinzia Cancellieri, Samantha Milanesi, Sabrina Badanai, Benedetta Savino, Francesco Bifari, Massimo Locati, Raffaella Bonecchi, and Elena Monica Borroni. "Control of Cytoskeletal Dynamics by β-Arrestin1/Myosin Vb Signaling Regulates Endosomal Sorting and Scavenging Activity of the Atypical Chemokine Receptor ACKR2." Vaccines 8, no. 3 (September 17, 2020): 542. http://dx.doi.org/10.3390/vaccines8030542.
Full textAbstract:
The atypical chemokine receptor ACKR2, formerly named D6, is a scavenger chemokine receptor with a non-redundant role in the control of inflammation and immunity. The scavenging activity of ACKR2 depends on its trafficking properties, which require actin cytoskeleton rearrangements downstream of a β-arrestin1-Rac1-PAK1-LIMK1-cofilin-dependent signaling pathway. We here demonstrate that in basal conditions, ACKR2 trafficking properties require intact actin and microtubules networks. The dynamic turnover of actin filaments is required to sustain ACKR2 constitutive endocytosis, while both actin and microtubule networks are involved in processes regulating ACKR2 constitutive sorting to rapid, Rab4-dependent and slow, Rab11-dependent recycling pathways, respectively. After chemokine engagement, ACKR2 requires myosin Vb activity to promote its trafficking from Rab11-positive recycling endosomes to the plasma membrane, which sustains its scavenging activity. Other than cofilin phosphorylation, induction of the β-arrestin1-dependent signaling pathway by ACKR2 agonists also leads to the rearrangement of microtubules, which is required to support the myosin Vb-dependent ACKR2 upregulation and its scavenging properties. Disruption of the actin-based cytoskeleton by the apoptosis-inducing agent staurosporine results in impaired ACKR2 internalization and chemokine degradation that is consistent with the emerging scavenging-independent activity of the receptor in apoptotic neutrophils instrumental for promoting efficient efferocytosis during the resolution of inflammation. In conclusion, we provide evidence that ACKR2 activates a β-arrestin1-dependent signaling pathway, triggering both the actin and the microtubule cytoskeletal networks, which control its trafficking and scavenger properties.
37
Tavares, Luciana P., Cristiana C. Garcia, Ana Paula F. Gonçalves, Lucas R. Kraemer, Eliza M. Melo, Fabrício M. S. Oliveira, Camila S. Freitas, et al. "ACKR2 contributes to pulmonary dysfunction by shaping CCL5:CCR5-dependent recruitment of lymphocytes during influenza A infection in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 4 (April 1, 2020): L655—L670. http://dx.doi.org/10.1152/ajplung.00134.2019.
Full textAbstract:
Inflammation triggered by influenza A virus (IAV) infection is important for viral clearance, induction of adaptive responses, and return to lung homeostasis. However, an exaggerated immune response, characterized by the overproduction of chemokines, can lead to intense lung injury, contributing to mortality. Chemokine scavenger receptors, such as ACKR2, control the levels of CC chemokines influencing the immune responses. Among the chemokine targets of ACKR2, CCL5 is important to recruit and activate lymphocytes. We investigated the role of ACKR2 during IAV infection in mice. Pulmonary ACKR2 expression was increased acutely after IAV infection preceding the virus-induced lung dysfunction. ACKR2-knockout (ACKR2−/−) mice were protected from IAV, presenting decreased viral burden and lung dysfunction. Mechanistically, the absence of ACKR2 resulted in augmented airway CCL5 levels, secreted by mononuclear and plasma cells in the lung parenchyma. The higher chemokine gradient led to an augmented recruitment of T and B lymphocytes, formation of inducible bronchus-associated lymphoid tissue and production of IgA in the airways of ACKR2−/− mice post-IAV. CCL5 neutralization in ACKR2−/− mice prevented lymphocyte recruitment and increased bronchoalveolar lavage fluid protein levels and pulmonary dysfunction. Finally, CCR5−/− mice presented increased disease severity during IAV infection, displaying increased neutrophils, pulmonary injury and dysfunction, and accentuated lethality. Collectively, our data showed that ACKR2 dampens CCL5 levels and the consequent recruitment of CCR5+ T helper 1 (Th1), T regulatory cells (Tregs), and B lymphocytes during IAV infection, decreasing pathogen control and promoting lung dysfunction in wild type mice. Therefore, ACKR2 is detrimental and CCR5 is protective during IAV infection coordinating innate and adaptive immune responses in mice.
38
Chatterjee, Madhumita. "Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology." Cells 11, no. 2 (January 9, 2022): 213. http://dx.doi.org/10.3390/cells11020213.
Full textAbstract:
The manifold actions of the pro-inflammatory and regenerative chemokine CXCL12/SDF-1α are executed through the canonical GProteinCoupledReceptor CXCR4, and the non-canonical ACKR3/CXCR7. Platelets express CXCR4, ACKR3/CXCR7, and are a vital source of CXCL12/SDF-1α themselves. In recent years, a regulatory impact of the CXCL12-CXCR4-CXCR7 axis on platelet biogenesis, i.e., megakaryopoiesis, thrombotic and thrombo-inflammatory actions have been revealed through experimental and clinical studies. Platelet surface expression of ACKR3/CXCR7 is significantly enhanced following myocardial infarction (MI) in acute coronary syndrome (ACS) patients, and is also associated with improved functional recovery and prognosis. The therapeutic implications of ACKR3/CXCR7 in myocardial regeneration and improved recovery following an ischemic episode, are well documented. Cardiomyocytes, cardiac-fibroblasts, endothelial lining of the blood vessels perfusing the heart, besides infiltrating platelets and monocytes, all express ACKR3/CXCR7. This review recapitulates ligand induced differential trafficking of platelet CXCR4-ACKR3/CXCR7 affecting their surface availability, and in regulating thrombo-inflammatory platelet functions and survival through CXCR4 or ACKR3/CXCR7. It emphasizes the pro-thrombotic influence of CXCL12/SDF-1α exerted through CXCR4, as opposed to the anti-thrombotic impact of ACKR3/CXCR7. Offering an innovative translational perspective, this review also discusses the advantages and challenges of utilizing ACKR3/CXCR7 as a potential anti-thrombotic strategy in platelet-associated cardiovascular disorders, particularly in coronary artery disease (CAD) patients post-MI.
39
Martini, Rachel, Kiel Telesford, Brittany Lord, Hiranmayi Ravichandran, Olivier Elemento, Nancy Manley, Michele Monteil, et al. "Abstract 6165: DARC/ACKR1 expression is associated with immune landscape changes among triple negative breast tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6165. http://dx.doi.org/10.1158/1538-7445.am2022-6165.
Full textAbstract:
Abstract Recent work defining the immune landscape across breast cancer (BC) subtypes have revealed that TNBC tumors have increased immunogenicity, and these increases in immune cell infiltration are associated with better prognosis and outcomes. Our recent work has proposed the Duffy Antigen Receptor for Chemokines (DARC), as a potential driver of immune regulation in breast tumors. DARC/ACKR1 is an atypical chemokine receptor that promiscuously binds both pro-inflammatory CC and pro-angiogenic CXC class chemokines and plays a role in chemokine gradient establishment both in circulation, and at sites of inflammation via chemokine transcytosis. In the BC context, we and others have reported DARC/ACKR1 protein expression on breast tumor epithelial cells by IHC and have also shown a range of gene expression in breast tumors from bulk RNAseq data in the TCGA cohort. Specifically, alongside CIBERSORT deconvolution of tumor associated immune cell populations, we have shown a strong positive correlation between DARC/ACKR1 gene expression and total tumor-associated leukocyte (TAL) abundance across all BC subtypes. To investigate the role of DARC/ACKR1 specifically in the TNBC tumor microenvironment (TME), we have analyzed (1) in silico bulk RNAseq data from two independent TNBC cohorts, (2) imaging mass cytometry data from TNBC patients and (3) murine model of DARC/ACKR1 BC progression in a basal-like BC transgenic mouse model. Our in silico data shows strong positive correlation of DARC/ACKR1 expression and TAL abundance, when DARC/ACKR1 expression is both dichotomized and analyzed as a continuous variable. Immune cell populations increasing with DARC/ACKR1 expression include B cell, T cell, monocyte and macrophage populations, which was consistent with our previous findings across all BC subtypes. IMC analysis of TNBC FFPE sections to determine protein expression of various immune and structural markers on the single-cell level between DARC/ACKR1 high or low expressing tumors show cells from DARC/ACKR1 high expressing tumors clustered distinctly from DARC/ACKR1 low expressing tumors. Image analysis also revealed increased infiltration among our DARC/ACKR1 high tumors. Finally, our murine model of DARC/ACKR1 in TNBC, shows that tumor development followed similar disease progression as human BC, following early through late-stage disease. DARC/ACKR1 deficient mice were found to have larger tumor volume and more palpable tumors, where DARC/ACKR1 expressing mice show co-localization of DARC and immune cell expression. This is the first work to describe the role of DARC/ACKR1 in the TNBC TME in bulk tumor transcriptomic data, spatial single-cell protein level data, and murine BC tumor model. Further investigation of factors that drive immune response in TNBC tumors, like DARC/ACKR1, may lead the way to novel therapeutic options or biomarkers for better outcomes for women with TNBC. Citation Format: Rachel Martini, Kiel Telesford, Brittany Lord, Hiranmayi Ravichandran, Olivier Elemento, Nancy Manley, Michele Monteil, Lisa Newman, Upender Manne, Clayton Yates, Melissa B. Davis. DARC/ACKR1 expression is associated with immune landscape changes among triple negative breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6165.
40
Zarca, Aurélien, Claudia Perez, Jelle van den Bor, Jan Paul Bebelman, Joyce Heuninck, Rianna J. F. de Jonker, Thierry Durroux, Henry F. Vischer, Marco Siderius, and Martine J. Smit. "Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization." Cells 10, no. 3 (March 11, 2021): 618. http://dx.doi.org/10.3390/cells10030618.
Full textAbstract:
Background: The atypical chemokine receptor 3 (ACKR3) belongs to the superfamily of G protein-coupled receptors (GPCRs). Unlike classical GPCRs, this receptor does not activate G proteins in most cell types but recruits β-arrestins upon activation. ACKR3 plays an important role in cancer and vascular diseases. As recruitment of β-arrestins is triggered by phosphorylation of the C-terminal tail of GPCRs, we studied the role of different potential phosphorylation sites within the ACKR3 C-tail to further delineate the molecular mechanism of internalization and trafficking of this GPCR. Methods: We used various bioluminescence and fluorescence resonance energy transfer-based sensors and techniques in Human Embryonic Kidney (HEK) 293T cells expressing WT or phosphorylation site mutants of ACKR3 to measure CXCL12-induced recruitment of β-arrestins and G-protein-coupled receptor kinases (GRKs), receptor internalization and trafficking. Results: Upon CXCL12 stimulation, ACKR3 recruits both β-arrestin 1 and 2 with equivalent kinetic profiles. We identified interactions with GRK2, 3 and 5, with GRK2 and 3 being important for β-arrestin recruitment. Upon activation, ACKR3 internalizes and recycles back to the cell membrane. We demonstrate that β-arrestin recruitment to the receptor is mainly determined by a single cluster of phosphorylated residues on the C-tail of ACKR3, and that residue T352 and in part S355 are important residues for β-arrestin1 recruitment. Phosphorylation of the C-tail appears essential for ligand-induced internalization and important for differential β-arrestin recruitment. GRK2 and 3 play a key role in receptor internalization. Moreover, ACKR3 can still internalize when β-arrestin recruitment is impaired or in the absence of β-arrestins, using alternative internalization pathways. Our data indicate that distinct residues within the C-tail of ACKR3 differentially regulate CXCL12-induced β-arrestin recruitment, ACKR3 trafficking and internalization.
41
Ewenighi-Amankwah, Chinwe Obianuju, Tanner Roach, Joseph Dufraine, Naiche Adler, and Jan Kitajewski. "Abstract C035: ACKR1 expression in stromal cells regulates immune infiltration in triple negative breast cancer." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C035. http://dx.doi.org/10.1158/1538-7755.disp22-c035.
Full textAbstract:
Abstract Triple-negative breast cancer (TNBC), a highly aggressive and metastatic subtype of breast cancer, lacks expression of the estrogen and progesterone receptors and amplification of HER2 and comprises 15-20% of all breast cancer. Incidence and mortality of TNBC are higher in Black Americans than in other racial/ethnic groups. Conversely, Black patients are underrepresented in clinical breast cancer drug trials, limiting our understanding of differential treatment responses. Leukocyte infiltration is a key modulator of TNBC outcome, and Black patients show immunological differences that may contribute to differential outcomes in TNBC. About 60-80% of Black Americans are homozygous for a polymorphism in the Atypical Chemokine Receptor 1 (ACKR1) promoter region that causes loss of ACKR1 expression on red blood cells, also known as the “Duffy-null” serotype. ACKR1 is expressed on tumor cells, red blood cells, and endothelial cells, and can act as a chemokine sink or chemokine concentrator, depending on the context. Whole-tumor RNA analysis shows that overall loss of ACKR1 expression in TNBC tumors correlates strongly with decreased survival, but it is unclear which ACKR1-expressing cell type(s) contribute to this effect. Under inflammatory conditions, ACKR1 expression in endothelial cells localizes chemotactic cytokines at the endothelial junction, and loss of endothelial ACKR1 blocks the ability of leukocytes to extravasate through the endothelial barrier into surrounding tissues. We hypothesized that loss of endothelial/stromal ACKR1 reduces immune infiltration and activation in TNBC and racial/ethnic differences in ACKR1 expression may contribute to health disparities. To determine the role of ACKR1 in tumor immune infiltration, we chose a syngeneic immunocompetent mouse model to incorporate species-matched stromal-tumor interactions. We orthotopically inoculated E0771.LMB cells, a C57BL6/J syngeneic TNBC cell line, into ACKR1null and ACKR1het female mice. Tumor growth was measured triweekly, and tumor mass was measured at the 28-day endpoint. To measure immune infiltration, we fluorescently stained representative tumor cryosections with CD45 to detect all classes of infiltrating hematopoietic cells involved in immune response. There was no significant difference in tumor volume and mass among the ACKR1null and ACKR1het controls. Tumors implanted in ACKR1het controls showed broadly infiltrated leukocytes clusters, while tumors in ACKR1nullhosts showed sparse and infrequent leukocyte infiltration. Conclusion: Stromal ACKR1 does not have a strong effect on primary tumor growth. Loss of stromal ACKR1 reduces infiltration of leukocytes into the tumor microenvironment even when ACKR1 is not manipulated in the tumor cells, suggesting that ACKR1 in endothelial or other stromal cells regulates immune response in TNBC. Impact: Understanding the immunogenic functions of ACKR1 allelic variation will elucidate mechanisms of racially distinct therapeutic response in TNBC, enhance precision oncology, and promote cancer health equity. Citation Format: Chinwe Obianuju Ewenighi-Amankwah, Tanner Roach, Joseph Dufraine, Naiche Adler, Jan Kitajewski. ACKR1 expression in stromal cells regulates immune infiltration in triple negative breast cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C035.
42
del Molino del Barrio, Irene, Georgina Wilkins, Annette Meeson, Simi Ali, and John Kirby. "Breast Cancer: An Examination of the Potential of ACKR3 to Modify the Response of CXCR4 to CXCL12." International Journal of Molecular Sciences 19, no. 11 (November 14, 2018): 3592. http://dx.doi.org/10.3390/ijms19113592.
Full textAbstract:
Upon binding with the chemokine CXCL12, the chemokine receptor CXCR4 has been shown to promote breast cancer progression. This process, however, can be affected by the expression of the atypical chemokine receptor ACKR3. Given ACKR3’s ability to form heterodimers with CXCR4, we investigated how dual expression of both receptors differed from their lone expression in terms of their signalling pathways. We created single and double CXCR4 and/or ACKR3 Chinese hamster ovary (CHO) cell transfectants. ERK and Akt phosphorylation after CXCL12 stimulation was assessed and correlated with receptor internalization. Functional consequences in cell migration and proliferation were determined through wound healing assays and calcium flux. Initial experiments showed that CXCR4 and ACKR3 were upregulated in primary breast cancer and that CXCR4 and ACKR3 could form heterodimers in transfected CHO cells. This co-expression modified CXCR4’s Akt activation after CXCL12’s stimulation but not ERK phosphorylation (p < 0.05). To assess this signalling disparity, receptor internalization was assessed and it was observed that ACKR3 was recycled to the surface whilst CXCR4 was degraded (p < 0.01), a process that could be partially inhibited with a proteasome inhibitor (p < 0.01). Internalization was also assessed with the ACKR3 agonist VUF11207, which caused both CXCR4 and ACKR3 to be degraded after internalization (p < 0.05 and p < 0.001), highlighting its potential as a dual targeting drug. Interestingly, we observed that CXCR4 but not ACKR3, activated calcium flux after CXCL12 stimulation (p < 0.05) and its co-expression could increase cellular migration (p < 0.01). These findings suggest that both receptors can signal through ERK and Akt pathways but co-expression can alter their kinetics and internalization pathways.
43
Johnsson, H., J. Cole, G. Wilson, M. Pingen, F. Mcmonagle, S. Holmes, I. Mcinnes, S. Siebert, and G. Graham. "SAT0351 CHEMOKINE PATHWAYS ARE ENRICHED IN PSORIATIC ARTHRITIS (PSA) SKIN LESIONS WITH INCREASED EXPRESSION OF ATYPICAL CHEMOKINE RECEPTOR 2 (ACKR2)." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1121.2–1122. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2980.
Full textAbstract:
Background:Skin in people with psoriasis has been comprehensively studied; uninvolved skin has abnormal gene expression. Less is known specifically about skin in PsA, the assumption being that it is identical to psoriasis. Chemokines and ACKR2 are among the upregulated genes in uninvolved psoriasis compared to healthy skin[1]. ACKR2 is a scavenging receptor of inflammatory CC chemokines and has been proposed as a regulator of cutaneous inflammation in psoriasis. It has not been studied in PsA.Objectives:To compare the transcriptome of PsA lesional, PsA uninvolved and healthy control skin and evaluate ACKR2 expression in PsA.Methods:Biopsies were taken from healthy control (HC) skin and paired lesional and uninvolved skin from patients with PsA. Libraries for bulk RNA sequencing were prepared from polyA selected RNA and sequenced on NovaSeq 6000. Sequencing data were analysed using Searchlight2. ACKR2 mRNA expression was validated by qPCR. RNAscope was used to localise ACKR2 expressing cells and sections were co-stained with podaplanin or stained in serial sections with CD45. Chemokine protein expression in skin was evaluated using Luminex technology.Results:Nine HC and 9 paired skin samples from patients with PsA were sequenced. The PsA skin lesions (PsA L) formed a distinct population in the transcriptomic principal component analysis (PCA) plot while HC and PsA uninvolved skin (PsA U) were overlapping. Only 15 genes were differentially expressed between HC and PsA U and none coded for chemokines. There were however significantly upregulated chemokines and receptors in PsA L. Unexpectely, ACKR2 was the 2ndmost upregulated chemokine receptor in PsA L with unchanged expression in PsA U compared with HC (PsA L vs HC log2fold 3.38, p.adj=9.51E-41; PsA L vs PsA U log2fold 3.58, p.adj=3.24E-45; PsA U vs HC log2fold -0.2, p.adj=0.732).The upregulation of ACKR2 in PsA L and unchanged expression in PsA U was confirmed by qPCR. RNAscope demonstrated strong expression of ACKR2 in the suprabasal layer of the epidermis in PsA L. In HC and PsA U, only occasional ACKR2 positive cells were seen in the epidermis. ACKR2 was expressed in lymphatic vessel walls but was not observed in CD45+ leukocytes.Provisional skin chemokine protein expression data showed poor correlation between mRNA levels and protein expression for the ACKR2 ligands CCL2, CCL3, CCL7, CCL8, CCL11, CCL13 and CCL22 in HC and PsA U, with negative correlation between ACKR2 mRNA expression and CCL2, CCL8 and CCL11 protein expression. In PsA L, chemokine mRNA correlated with protein expression, but protein expression of chemokine ligands did not correlate with ACKR2 expression.Conclusion:This data set shows expected upregulation of chemokines and their receptors in PsA L but relatively unchanged gene expression in PsA U, which contrasts to previous studies in psoriasis. Notably, this study demonstrates a strong upregulation of ACKR2 in keratinocytes in PsA L, with unchanged expression in PsA U. The RNA expression and preliminary protein data suggest that ACKR2 has little effect on the levels of its ligands in PsA skin lesions. However, this study may have missed local effects of ACKR2 in the epidermis.References:[1]Singh, M.D., et al.,Elevated expression of the chemokine-scavenging receptor D6 is associated with impaired lesion development in psoriasis.Am J Pathol, 2012.181(4): p. 1158-64.Acknowledgments:Funded by the Chief Scientist Office and a private donation to the University of Glasgow. Dr Sabarinadh Chilaka helped to prepare libraries for RNA sequencing.Disclosure of Interests:Hanna Johnsson: None declared, John Cole: None declared, Gillian Wilson: None declared, Marieke Pingen: None declared, Fiona McMonagle: None declared, Susan Holmes: None declared, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Gerard Graham: None declared
44
Cebo, Malgorzata, Kristina Dittrich, Xiaoqing Fu, Mailin C. Manke, Frederic Emschermann, Johannes Rheinlaender, Hendrik von Eysmondt, et al. "Platelet ACKR3/CXCR7 favors antiplatelet lipids over an atherothrombotic lipidome and regulates thromboinflammation." Blood 139, no. 11 (March 17, 2022): 1722–42. http://dx.doi.org/10.1182/blood.2021013097.
Full textAbstract:
Abstract Platelet ACKR3/CXCR7 surface expression is enhanced and influences prognosis in coronary artery disease (CAD) patients, who exhibit a distinct atherothrombotic platelet lipidome. Current investigation validates the potential of ACKR3/CXCR7 in regulating thromboinflammatory response through its impact on the platelet lipidome. CAD patients with enhanced platelet ACKR3/CXCR7 expression exhibited reduced aggregation. Pharmacological CXCR7 agonist (VUF11207) significantly reduced prothrombotic platelet response in blood from acute coronary syndrome patients ex vivo. CXCR7 agonist administration reduced thrombotic functions and thromboinflammatory plateletleukocyte interactions post–myocardial infarction and arterial injury in vivo. ACKR3/CXCR7 ligation did not affect surface availability of surface receptors, coagulation profile, bleeding time, plasma-dependent thrombin generation (thrombinoscopy), or clot formation (thromboelastography) but counteracted activation-induced phosphatidylserine exposure and procoagulant platelet-assisted thrombin generation. Targeted (micro-UHPLC-ESI-QTrap-MS/MS) and untargeted (UHPLCESI-QTOF-MS/MS) lipidomics analysis revealed that ACKR3/CXCR7 ligation favored generation of antithrombotic lipids (dihomo-γ-linolenic acid [DGLA], 12-hydroxyeicosatrienoic acid [12-HETrE]) over cyclooxygenase-1 (COX-1) or 12-lipoxygenase (12-LOX) metabolized prothrombotic and phospholipase-derived atherogenic lipids in healthy subjects and CAD patients, contrary to antiplatelet therapy. Through 12-HETrE, ACKR3/CXCR7 ligation coordinated with Gαs-coupled prostacyclin receptor to trigger cyclic adenosine monophosphate/protein kinase A–mediated platelet inhibition. ACKR3/CXCR7 ligation reduced generation of lipid agonists and lipid signaling intermediates, which affected calcium mobilization, intracellular signaling, and consequently platelet interaction with physiological matrices and thromboinflammatory secretome. This emphasized its functional dichotomy from prothrombotic CXCR4. Moreover, CXCR7 agonist regulated heparin-induced thrombocytopenia–sera/immunoglobulin G–triggered platelet and neutrophil activation, heparin-induced platelet aggregation, generation of thromboinflammatory lipids, platelet-neutrophil aggregate formation, and thromboinflammatory secretion ex vivo. Therefore, ACKR3/CXCR7 may offer a novel therapeutic strategy in acute/chronic thromboinflammation exaggerated cardiovascular pathologies and CAD.
45
Smit, Martine J., Géraldine Schlecht-Louf, Maria Neves, Jelle van den Bor, Petronila Penela, Marco Siderius, Françoise Bachelerie, and Federico Mayor. "The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting." Annual Review of Pharmacology and Toxicology 61, no. 1 (January 6, 2021): 541–63. http://dx.doi.org/10.1146/annurev-pharmtox-010919-023340.
Full textAbstract:
Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.
46
E-Zereen, Jannat, and Gwyneth Ingram. "A Possible Involvement of ACR4, a Receptor Like Kinase, in Plant Defence Mechanism." Bangladesh Pharmaceutical Journal 15, no. 2 (November 13, 2012): 127–30. http://dx.doi.org/10.3329/bpj.v15i2.12576.
Full textAbstract:
Many developmentally important Receptor Like Kinases (RLKs), also known as receptor kinases have been shown to play independent roles in plant defence. In order to investigate the role of Arabidopsis CRINKLY4 (ACR4) in plant defence mechanism, pathogen challenge experiments were carried out. It was found that ACR4 knockout leaves show reduced susceptibility to the necrotrophic pathogen, Botrytis cinerea. It is therefore possible that the ACR4 receptor might interact with other proteins that regulate specific defence responses. Reduced susceptibility of ACR4 mutant to B. cinerea could also be due to the possible epidermal defect of acr4 leaves. A detailed study of the cuticular lipid composition of acr4 leaves may help ascertain whether epidermal defects in acr4 leaves are responsible for resistance against B. cinerea. DOI: http://dx.doi.org/10.3329/bpj.v15i2.12576 Bangladesh Pharmaceutical Journal 15(2): 127-130, 2012
47
Neves, Maria, Viviana Marolda, Federico Mayor, and Petronila Penela. "Crosstalk between CXCR4/ACKR3 and EGFR Signaling in Breast Cancer Cells." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11887. http://dx.doi.org/10.3390/ijms231911887.
Full textAbstract:
A better understanding of the complex crosstalk among key receptors and signaling pathways involved in cancer progression is needed to improve current therapies. We have investigated in cell models representative of the major subtypes of breast cancer (BC) the interplay between the chemokine CXCL12/CXCR4/ACKR3 and EGF receptor (EGFR) family signaling cascades. These cell lines display a high heterogeneity in expression profiles of CXCR4/ACKR3 chemokine receptors, with a predominant intracellular localization and different proportions of cell surface CXCR4+, ACKR3+ or double-positive cell subpopulations, and display an overall modest activation of oncogenic pathways in response to exogenous CXCL12 alone. Interestingly, we find that in MDA-MB-361 (luminal B subtype, Her2-overexpressing), but not in MCF7 (luminal A) or MDA-MB-231 (triple negative) cells, CXCR4/ACKR3 and EGFR receptor families share signaling components and crosstalk mechanisms to concurrently promote ERK1/2 activation, with a key involvement of the G protein-coupled receptor kinase 2 (GRK2) signaling hub and the cytosolic tyrosine kinase Src. Our findings suggest that in certain BC subtypes, a relevant cooperation between CXCR4/ACKR3 and growth factor receptors takes place to integrate concurrent signals emanating from the tumor microenvironment and foster cancer progression.
48
Yue, Kun, Priyanka Sandal, Elisabeth L. Williams, Evan Murphy, Elisabeth Stes, Natalia Nikonorova, Priya Ramakrishna, et al. "PP2A-3 interacts with ACR4 and regulates formative cell division in the Arabidopsis root." Proceedings of the National Academy of Sciences 113, no. 5 (January 20, 2016): 1447–52. http://dx.doi.org/10.1073/pnas.1525122113.
Full textAbstract:
In plants, the generation of new cell types and tissues depends on coordinated and oriented formative cell divisions. The plasma membrane-localized receptor kinase ARABIDOPSIS CRINKLY 4 (ACR4) is part of a mechanism controlling formative cell divisions in the Arabidopsis root. Despite its important role in plant development, very little is known about the molecular mechanism with which ACR4 is affiliated and its network of interactions. Here, we used various complementary proteomic approaches to identify ACR4-interacting protein candidates that are likely regulators of formative cell divisions and that could pave the way to unraveling the molecular basis behind ACR4-mediated signaling. We identified PROTEIN PHOSPHATASE 2A-3 (PP2A-3), a catalytic subunit of PP2A holoenzymes, as a previously unidentified regulator of formative cell divisions and as one of the first described substrates of ACR4. Our in vitro data argue for the existence of a tight posttranslational regulation in the associated biochemical network through reciprocal regulation between ACR4 and PP2A-3 at the phosphorylation level.
49
Fichou, Yann, Isabelle Berlivet, Gaëlle Richard, Christophe Tournamille, Lilian Castilho, and Claude Férec. "Defining Blood Group Gene Reference Alleles by Long-Read Sequencing: Proof of Concept in the ACKR1 Gene Encoding the Duffy Antigens." Transfusion Medicine and Hemotherapy 47, no. 1 (December 11, 2019): 23–32. http://dx.doi.org/10.1159/000504584.
Full textAbstract:
Background: In the novel era of blood group genomics, (re-)defining reference gene/allele sequences of blood group genes has become an important goal to achieve, both for diagnostic and research purposes. As novel potent sequencing technologies are available, we thought to investigate the variability encountered in the three most common alleles of ACKR1, the gene encoding the clinically relevant Duffy antigens, at the haplotype level by a long-read sequencing approach. Materials and Methods: After long-range PCR amplification spanning the whole ACKR1 gene locus (∼2.5 kilobases), amplicons generated from 81 samples with known genotypes were sequenced in a single read by using the Pacific Biosciences (PacBio) single molecule, real-time (SMRT) sequencing technology. Results: High-quality sequencing reads were obtained for the 162 alleles (accuracy >0.999). Twenty-two nucleotide variations reported in databases were identified, defining 19 haplotypes: four, eight, and seven haplotypes in 46 ACKR1*01, 63 ACKR1*02, and 53 ACKR1*02N.01 alleles, respectively. Discussion: Overall, we have defined a subset of reference alleles by third-generation (long-read) sequencing. This technology, which provides a “longitudinal” overview of the loci of interest (several thousand base pairs) and is complementary to the second-generation (short-read) next-generation sequencing technology, is of critical interest for resolving novel, rare, and null alleles.
50
Saaber, Friederike, Dagmar Schütz, Elke Miess, Philipp Abe, Srinidhi Desikan, Praveen Ashok Kumar, Sara Balk, et al. "ACKR3 Regulation of Neuronal Migration Requires ACKR3 Phosphorylation, but Not β-Arrestin." Cell Reports 26, no. 6 (February 2019): 1473–88. http://dx.doi.org/10.1016/j.celrep.2019.01.049.
Full text