Rabbit Anti-Human ACKR2 (internal) Polyclonal antibody

A recent genome-wide association study (GWAS) of 59 cerebrospinal fluid (CSF) proteins with a connection to Alzheimer's disease (AD) demonstrated an association between increased levels of chemokine ligand 2 (CCL2) with an atypical chemokine receptor chemokine-binding protein 2 variant V41A (ACKR2-V41A; rs2228467). High levels of CCL2 are associated with increased risk of AD development as well as other inflammatory diseases. In this study we characterized the biological function of the ACKR2-V41A receptor compared to the wild type allele by measuring its ligand binding affinity, CCL2 scavenging efficiency, and cell activation sensitivity. We transfected Chinese hamster ovary cells with plasmids carrying wild type ACKR2 (ACKR2-WT) or the mutant ACKR2-V41A receptor. Binding affinity assays showed that ACKR2-V41A has a lower binding affinity for CCL2 and CCL4 than ACKR2-WT. CCL2 scavenging results aligned with binding affinity assays, with ACKR2-V41A cells scavenging CCL2 with a lower efficiency than ACKR2-WT. Cell activation assays also showed that ACKR2-V41A cells had significantly lower receptor upregulation (beta -Arrestin-dependent signaling pathway) upon stimulation compared to ACKR2-WT cells. These findings provide molecular and biological mechanistic insights into the GWAS association of ACKR2-V41A with increased levels of CCL2 in CSF and possibly other chemokine ligands. Increased CCL2 levels are associated with accelerated cognitive decline and increased risk of AD. Understanding how this atypical chemokine receptor allele increases serum markers of inflammation could lead to novel therapeutic solutions for AD.

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. CCRL2, a presumed member of the atypical chemokine receptor family, plays a key role in lung dendritic cell trafficking to peripheral lymph nodes. Recent studies have reported the expression of CCRL2 in different human cancer cell lines and tissues. However, its function and expression in prostate cancer has not been previously addressed.