Atypical chemokine receptor d6

Atypical chemokine receptors (ACKRs) form a small subfamily of receptors (ACKR1-4) unable to trigger G protein-dependent signaling in response to their ligands. They do, however, play a crucial regulatory role in chemokine biology by capturing, scavenging or transporting chemokines, thereby regulating their availability and signaling through classical chemokine receptors. ACKRs add thus another layer of complexity to the intricate chemokine-receptor interaction network. Recently, targeted approaches and screening programs aiming at reassessing chemokine activity towards ACKRs identified several new pairings such as the dimeric CXCL12 with ACKR1, CXCL2, CXCL10 and CCL26 with ACKR2, the viral broad-spectrum chemokine vCCL2/vMIP-II, a range of opioid peptides and PAMP-12 with ACKR3 as well as CCL20 and CCL22 with ACKR4...

Chemokines exert crucial roles in inducing immune responses through ligation to their canonical receptors. Besides these receptors, there are other atypical chemokine receptors (ACKR1-4) that can bind to a wide range of chemokines and carry out various functions in the body. ACKR2, due to its ability to bind various CC chemokines, has attracted much attention during the past few years. ACKR2 has been shown to be expressed in different cells, including trophoblasts, myeloid cells, and especially lymphoid endothelial cells...

The resolution of inflammation facilitates proper wound healing and limits tissue repair short of exaggerated fibrotic scarring. The atypical chemokine receptor (ACKR)2/D6 scavenges inflammatory chemokines, while IFN-β is a recently unveiled pro-resolving cytokine. Both effector molecules limit acute inflammatory episodes and promote their resolution in various organs. Here, we found fibrotic skin lesions from ACKR2-/- mice presented increased epidermal and dermal thickening, atrophy of the subcutaneous adipose tissue, augmented disorientation of collagen deposition, and enhanced deformation and loss of hair follicles compared to WT counterparts...

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...

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...

The anti-tumor activities of some members of the chemokine family are often overcome by the functions of many chemokines that are strongly and causatively linked with increased tumor progression. Being key leukocyte attractants, chemokines promote the presence of inflammatory pro-tumor myeloid cells and immune-suppressive cells in tumors and metastases. In parallel, chemokines elevate additional pro-cancerous processes that depend on cell motility: endothelial cell migration (angiogenesis), recruitment of mesenchymal stem cells (MSCs) and site-specific metastasis...

OBJECTIVE: The purpose of this study was to investigate the expression of atypical chemokine receptor 2 (ACKR2, D6) in different types of preeclampsia (PE) and its effects on trophoblast proliferation and apoptosis. METHODS: The subjects were divided into four groups: early-onset PE group (EOPE, n = 30), late-onset PE group (LOPE, n = 30), preterm birth group (PB, n = 30), and normal group (N, n = 30). The expression of ACKR2 in placentas was evaluated using immunohistochemistry, qRT-PCR, and Western blot...

Atypical chemokine receptors have recently emerged as important molecular players in health and diseases; they affect chemokine availability and function and impact a multitude of pathophysiological events, including the tumorigenesis process. This family of atypical receptors comprises five members: ACKR1/DARC, ACKR2/D6, ACKR3/CXCR7, ACKR4/CCRL1, and ACKR5/CCRL2. This work evaluated the differential expression of these receptors in prostate cancer using quantitative PCR. Further evaluation of CCRL2 at the protein level confirmed its overexpression in a metastatic cell line and in malignant prostatic tissues from patients...

The atypical chemokine receptor 2 (ACKR2), also named D6, regulates local levels of inflammatory chemokines by internalization and degradation. To explore potential anti-inflammatory functions of ACKR2 in glomerulonephritis, we induced autologous nephrotoxic nephritis in C57/BL6 wild-type and Ackr2-deficient mice. Renal ACKR2 expression increased and localized to interstitial lymphatic endothelium during nephritis. At two weeks Ackr2-/- mice developed increased albuminuria and urea levels compared to wild-type mice...

The engulfment of apoptotic polymorphonuclear cells (PMN) during the resolution of inflammation leads to macrophage reprogramming culminating in reduced proinflammatory and increased anti-inflammatory mediator secretion. The atypical chemokine receptor D6/ACKR2 is expressed on apoptotic PMN and plays an important role in regulating macrophage properties during and after engulfment. In this study, we found that the inflammatory chemokine CCL5 is mostly retained (75%) during the resolution of zymosan A peritonitis in mice...

Inflammatory reactions occurring in the central nervous system (CNS), known as neuroinflammation, are key components of the pathogenic mechanisms underlying several neurological diseases. The chemokine system plays a crucial role in the recruitment and activation of immune and non-immune cells in the brain, as well as in the regulation of microglia phenotype and function. Chemokines belong to a heterogeneous family of chemotactic agonists that signal through the interaction with G protein-coupled receptors (GPCRs)...

The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity...

Inflammatory chemokines produced in the placenta can direct the migration of placental leukocytes using chemokine receptors that decorate the surface of these cells. Fetal trophoblasts can also express receptors for inflammatory chemokines, and they are one of the few cell types that express atypical chemokine receptor 2 (ACKR2), previously known as D6. ACKR2 binds many inflammatory CC chemokines but cannot stimulate cell migration or activate signaling pathways used by conventional chemokine receptors. Existing evidence suggests that ACKR2 is a specialized chemokine scavenger, but its function in primary human trophoblasts has not been explored...

Murine zymosan-induced peritonitis is the model most frequently used to study resolution of inflammation. However, the antigen-induced peritonitis model may be better suited for studying resolution of inflammation and the adaptive phase that follows. The objective of this study was to provide an evaluation of the kinetics of cells and mediators during induction, resolution and the adaptive immune phases of a murine antigen-induced inflammation. Female C57BL/6 mice were immunized twice subcutaneously with mBSA and three weeks after the initial immunization they were injected intraperitoneally (i...

The aim of this study was to determine the frequency of axillary lymph node (ALN) metastasis of early breast cancers by evaluating the status of DARC, D6 and CCX-CKR and the levels of VEGF and MMP-9. The status of DARC, D6 and CCX-CKR and the levels VEGF and MMP-9 were evaluated in ALN- (n = 130) and ALN + (n = 88) patients with T1 breast cancer by immunohistochemical staining. For ALN, likelihood ratio χ (2)-tests were used for univariate analysis and logistic regression for multivariate analysis. Univariate analysis identified the nuclear grade, VEGF and MMP-9 expression and absence of DARC, D6 and CCX-CKR as predictors of ALN involvement...

D6 is an atypical chemokine receptor acting as a decoy and scavenger for inflammatory CC chemokines expressed in lymphatic endothelial cells. Here, we report that D6 is expressed in Kaposi sarcoma (KS), a tumor ontogenetically related to the lymphatic endothelium. Both in human tumors and in an experimental model, D6 expression levels were inversely correlated with tumor aggressiveness and increased infiltration of proangiogenic macrophages. Inhibition of monocyte recruitment reduced the growth of tumors, while adoptive transfer of wild-type, but not CCR2(-/-) macrophages, increased the growth rate of D6-competent neoplasms...

Apart from their major function in the coordination of leukocyte recruitment, chemokines, in cooperation with their receptors, have been implicated in the progression of various diseases including different types of cancer, affecting survival, proliferation and metastasis. A complex network of chemokines and receptors exists in the tumor microenvironment and affects tumor development in various ways where chemokines activate typical signalling pathways by binding to the respective receptors. The identification and characterization of a group of atypical chemokine receptors [D6, Duffy antigen receptor for chemokines (DARC), ChemoCentryx chemokine receptor (CCX-CKR) and CXCR7] which appear to use unique biochemical properties to regulate the biological activities of these chemokines, is useful in the effort to therapeutically manipulate chemokines in a broad spectrum of diseases in which these chemokines play a critical role...

Chemokines and their receptors have been shown to play a vital role in lung cancer progression. D6 is an atypical chemokine receptor which is able to internalize and degrade chemokines. To investigate the potential role of D6 in lung cancer, we established D6-overexpressing A549 lung cancer cell lines by the transfection of human D6 cDNA. Results showed that D6 inhibited the proliferation of cancer cells in vitro and tumorigenesis in vivo. We also determined chemokine levels in the supernatant and showed that a number of chemokines (CCL2/4/5) had significantly decreased protein levels in D6-overexpressing cells compared with the controls, whereas no significant changes in mRNA expression levels of these chemokines were detected...

Chemokines, acting on their cognate receptors on infiltrating leukocytes, drive the inflammatory response. We have been interested in determining roles and potential mechanisms for the atypical chemokine-scavenging receptor D6 in the regulation of inflammation. In this study, we show that a psoriasis-like pathology that arises in inflamed skins of D6-deficient mice is characterized by a massive and aberrant localization of neutrophils to the dermal/epidermal junction, which is associated with development of the pathology...

Chemokines promote the recruitment of leukocytes to sites of infection and inflammation by activating conventional heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). Chemokines are also recognized by a set of atypical chemokine receptors (ACRs), which cannot induce directional cell migration but are required for the generation of chemokine gradients in tissues. ACRs are presently considered "silent receptors" because no G protein-dependent signaling activity is observed after their engagement by cognate ligands...