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- Table of Contents
Facts about Atypical chemokine receptor 2.
Upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein- independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) via a RAC1-PAK1- LIMK1 signaling pathway. Activation of this pathway results in up- regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficacy in chemokine uptake and degradation.
Human | |
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Gene Name: | ACKR2 |
Uniprot: | O00590 |
Entrez: | 1238 |
Belongs to: |
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G-protein coupled receptor 1 family |
ACKR2; C-C chemokine receptor D6; CCBP2; CCR10CCR9D6CC-chemokine-binding receptor JAB61; chemokine (C-C) receptor 9; chemokine binding protein 2; Chemokine receptor CCR-10; Chemokine receptor CCR-9; chemokine receptor D6; chemokine-binding protein 2; Chemokine-binding protein D6; CMKBR9; CMKBR9chemokine (C-C motif) receptor 9; D6; hD6; MGC126678; MGC138250
Mass (kDA):
43.443 kDA
Human | |
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Location: | 3p22.1 |
Sequence: | 3; NC_000003.12 (42809445..42867286) |
Found in endothelial cells lining afferent lymphatics in dermis and lymph nodes. Also found in lymph nodes subcapsular and medullary sinuses, tonsillar lymphatic sinuses and lymphatics in mucosa and submucosa of small and large intestine and appendix. Also found in some malignant vascular tumors. Expressed at high levels in Kaposi sarcoma-related pathologies. Expressed on apoptotic neutrophils (at protein level). Expressed primarily in placenta and fetal liver, and found at very low levels in the lung and lymph node.
Early endosome. Recycling endosome. Cell membrane; Multi-pass membrane protein. Predominantly localizes to endocytic vesicles, and upon stimulation by the ligand is internalized via clathrin-coated pits. Once internalized, the ligand dissociates from the receptor, and is targeted to degradation while the receptor is recycled back to the cell membrane.
The ACKR2 marker can be found in many biological assays. These assays use monoclonal or polyclonal antibodies to detect ACKR2. The ACKR2 is a receptor for chemokines that can either act as a decoy or an interceptor. Boster Bio uses rabbit and mouse to develop its antibodies. For research purposes, ACKR2 is also referred to as the interceptor receptor, chemokine scavenger receptor, or chemokine decoy receptor.
During pregnancy, a receptor called ACKR2 is expressed on the surface of human trophoblasts. It is believed to regulate trophoblast responses to extracellular chemokines and may also suppress the activity of coexpressed conventional chemokine receptors (CCR1 and CCR4). The reciprocal regulation of ACKR2 and conventional chemokine receptors may regulate trophoblast responses to chemokines, possibly switching their migratory and scavenging potential.
A study in mice found that deficient in ACKR2 suppressed cutaneous inflammation, increased necrotic areas, and enhanced inflammatory activity. In addition, ACKR2-/ mice showed increased angiogenesis and a higher number of leukocytes, indicating that ACKR2 promotes the resolution of cutaneous inflammation by facilitating chemokine clearance. Thus, ACKR2 may play an important role in regulating chemokine concentration in the skin.
ACKR2 has been shown to regulate chemokine concentration through its ability to internalize inflammatory cytokines and recycle them to the cell surface for destruction. Moreover, it can scavenge additional inflammatory chemokines, and its expression is widespread on leukocytes and microglia, which are cells in the CNS. Researchers have found that non-synonymous mutations in the gene are associated with an increased risk of breast cancer and testicular leukemia.
The mechanisms underlying the development of reproductive phenotypes in mice lacking ACKR2 are unknown. However, it is likely that defective scavenging is responsible for the increase in CCL2 levels in pregnant Ackr2-deficient mice. Additionally, the loss of ACKR2 has been associated with several reproductive phenotypes, including an increased concentration of CCL2 in the blood. Besides, a lack of ACKR2 results in increased CCL2 concentration and alterations in placenta structure at E14.
We tested the sensitivity of a mouse model to bleomycin. A lack of ACKR2 led to an elevated level of bleomycin-induced chemokines in the lung. In addition, a reduction in ACKR2 activity in mice resulted in reduced bleomycin-induced lung injury. These results suggest that a lack of ACKR2 may modify the microenvironment for the Th27 response.
Several studies have suggested a positive correlation between ACKR2 expression and tumor invasion in cancers. In breast cancer, ACKR2 expression has been associated with TNM stage, lymph node metastasis, and tumor size. In cervical and gastric cancer, ACKR2 expression has been associated with tumor size and histological grade. In addition, the receptor is associated with tumor recurrence. Despite this apparent conflict, future studies need to verify these results to determine whether or not this protein can be used to predict cancer progression or to detect the effects of therapies.
We also looked at the role of ACKR2 in chemokine clearance. We found that ACKR2-WT had a Kd of 3.4, whereas ACKR2-V41A had a Kd of 3.3. In both models, the amino acid 41 was located in the middle right. This difference in Kd between the two variants could contribute to the differences observed in the studies.
In addition to regulating the inflammatory response, ACKR2 is required for efficient chemokine clearance. ACKR2 also scavenges inflammatory chemokines and recycles them back to the cell surface. ACKR2 is expressed on a wide variety of cells, including leukocytes. In addition to its role in inflammatory responses, ACKR2 is important for gut inflammation and cancer progression. Inflammatory chemokines are known to promote tumor progression.
PsA skin lesions and uninvolved skin showed abnormal gene expression. In the uninvolved skin, chemokines are upregulated. Although this marker has not been investigated in PsA, it may be a potential target for a therapy. Despite its psoriasis-specific action, ACKR2 is a scavenger receptor of inflammatory CC chemokines.
The ACKR2 receptor plays distinct roles in inflammatory and resting conditions. During rest and inflammation, ACKR2 regulates macrophage proximity to lymphatic vessels. By limiting the interaction between inflammatory cells and lymphatic endothelial cells, ACKR2-deficient mice display ineffective antigen presentation from inflamed sites. In addition, ACKR2 is upregulated in response to interleukin-6 and interferon-g, suggesting a role in regulating lymphangiogenesis.
ACKR2 is a receptor found in lymphatic tissues and plays a crucial role in regulating immune response and inflammation. It is also essential for the discrimination of immature/mature dendritic cells by LECs. However, further experimental studies are needed to understand its role in cancer. Despite its multiple functions, it is still unclear whether it is a potential target for cancer immunotherapy.
ACKR2 has an anti-inflammatory function and promotes the migration of DC to the LN, which is critical for the adaptive response to immune attack but may also be detrimental in some autoimmune diseases. Furthermore, ACKR2 controls the production of IL-17, an important cytokine that drives inflammatory diseases. In a recent study, Lee et al. found that Ackr2-/ mice displayed increased density of LVs both during rest and in popliteal LNs. Furthermore, in E15.5 embryonic mice, macrophages were observed in close proximity to developing LVs.
ACKR2-V41A alters chemokine levels by disrupting their homeostasis. Inflammation is associated with an increased risk of AD. Infection-related chemoreceptors are a major cause of chronic inflammation. ACKR2-V41A is a key component in the regulation of inflammation. Therefore, a gene variant affecting the expression of this receptor is associated with increased risk for AD and breast cancer.
IFN-g is essential for enhancing ACKR2 expression in distant skin sites. This effect of IFN-g on ACKR2 expression may protect psoriasis-free skin from further inflammation. Further research is needed to identify whether ACKR2 is important in regulating psoriatic inflammation in a clinical setting. So, let's explore this intriguing possibility.
In addition to its important role in the regulation of immune responses, ACKR2 also regulates renal function. In mice, it is believed that ACKR2 functions as an anti-inflammatory molecule that prevents the migration of T cells to lymph nodes. Furthermore, ACKR2 has a nonredundant role in leukocyte adhesion to activated vascular endothelium. In the laboratory, however, ACKR2 expression does not influence the recruitment of immune cells. This explains why anti-CKR2 antibody is a viable therapeutic strategy.
The primary role of chemokine receptors is to regulate leukocyte recruitment and migration in tissues. Inflammatory chemokines activate integrins on cell surfaces. Therefore, they require high-affinity binding to achieve transendothelial migration. Additionally, chemokines trigger a cascade of cellular adhesion which is essential for leukocyte recruitment. So, while this approach is not effective, it can be helpful to determine the role of chemotactic chemokines in leukocyte migration.
ACKR2 is a molecular marker that regulates LV density. It competes with CCR2 for binding CCL2, a chemokine that induces monocyte infiltration in LNs. Ackr2-/ mice display increased LV density in resting and in vivo conditions. They also show increased angiogenesis and leukocyte infiltration. These findings suggest that ACKR2 is critical for promoting skin inflammation resolution by facilitating chemokine clearance.
ACKR2 has been found to be expressed on LECs and regulates chemokine levels and leukocyte migration. It is also thought to play a role in the resolution of inflammation in various pathological conditions. Therefore, ACKR2 is a potential therapeutic target. Inhibiting its expression could attenuate skin inflammation. This is good news for those suffering from inflammatory skin conditions.
ACKR2 regulates chemokine levels around afferent LVs. It also regulates lymphocyte trafficking and lymphatic vessel density. Further studies are needed to determine if it can be used as a prognostic marker for cancer. Because ACKR2 activity on lymphatics inhibits or promotes adaptive immune responses, it may also influence the spread of cancer cells.
PMID: 9364936 by Bonini J.A., et al. Cloning, expression, and chromosomal mapping of a novel human CC- chemokine receptor (CCR10) that displays high-affinity binding for MCP-1 and MCP-3.
PMID: 9405404 by Nibbs R.J.B., et al. Cloning and characterization of a novel promiscuous human beta- chemokine receptor D6.