ACKR1 Membrane Protein Introduction

Introduction of ACKR1

Atypical chemokine receptor 1 (ACKR1) is a new standardized name for the Duffy Antigen Receptor for Chemokines (DARC), and it can bind specifically to many pro-inflammatory chemokines. As a member of the 7-transmembrane (7 TM) domain protein superfamily, ACKR1 is unexpectedly unable to signal through heterotrimeric G proteins. ACKR1 is mainly expressed in erythrocytes, endothelial cells of post-capillary venules, and in cerebellar Purkinje cells, but it cannot be expressed in leukocytes. In erythrocytes, ACKR1 is helpful to shape and buffer chemokine concentration gradients during inflammatory responses by scavenging chemokines. On endothelial cells, ACKR1 is thought to mediate transcytosis of chemokines for subsequent presentation to blood leukocytes.

Function of ACKR1 Membrane Protein

ACKR1 is an atypical chemokine receptor that binds promiscuously to various inflammatory CC and CXC chemokines, including CCL2, CCL5, CCL17, CXCL1, CXCL5, and CXCL8, without signaling through G proteins. Acting through typical G protein-coupled chemokine receptors, ACKR1 ligands can induce the activation and migration of many leucocyte subsets, including monocytes, T cells, and neutrophils into the vessel wall, and play a pathogenic role during atherosclerosis development. ACKR1 may mediate transcytosis and scavenging the inflammatory chemokines. As a regulator of inflammation, ACKR1 has been examined in various contexts, including sepsis, malaria infection, HIV, cancer, and renal failure; however, a role in chronic inflammatory pathologies has not yet been defined. It has been suggested that ACKR1 may have diagnostic and therapeutic implications in cardiovascular diseases since ACKR1 is expressed by erythrocytes, which are present within atherosclerotic plaques and may promote plaque growth and instability.

Fig.1 Role of chemokines and chemokine receptors in the bone marrow hematopoietic niche. ACKR1 expressed by NECs binds an unknown receptor on HSCs and regulates hematopoiesis, in particular, myeloid differentiation. (Locati, 2017)

Application of ACKR1 Membrane Protein in Literature

1. Horuk R. The Duffy Antigen Receptor for Chemokines DARC/ACKR1. Frontiers in Immunology. 2015, 6: 279. PubMed ID: 26097477
   
   

   This article finds that the parallels to the CCR5 delta32 mutation as a protective factor in infection by HIV and the successful development of a CCR5 inhibitor to treat AIDS are striking and we envisage that the development of a DARC inhibitor might also work for P. vivax-induced malaria.

2. Rappoport N., et al. Correlation between 'ACKR1/DARC null' polymorphism and benign neutropenia in Yemenite Jews. Br J Haematol. 2015, 170(6): 892-5. PubMed ID: 25817587
   
   

   This article suggests the strong and statistically significant correlation between C/C homozygosity of a specific SNP (rs2814778) and the clinical manifestation of benign neutropenia in Yemenite Jew.

3. Wan W., et al. Atypical chemokine receptor 1 deficiency reduces atherogenesis in ApoE-knockout mice. Cardiovasc Res. 2015, 106(3): 478-87. PubMed ID: 25858253
   
   

   This article suggests that Ackr1 plays a critical role in chronic inflammation, in particular in the ApoE^-/- mouse model of atherogenesis. The mechanism may involve control of cytokine and chemokine balance in blood and plaque, including regulation of the important T cell and macrophage-targeted chemokine Ccl2. Ackr1 may be considered as a potential target for therapeutic development in atherosclerosis.

4. Schneider E.H., et al. Regulation of motor function and behavior by atypical chemokine receptor 1. Behavior genetics. 2014, 44(5): 498-515. PubMed ID: 24997773
   
   

   This article reveals that Ackr1 plays an important role in regulating the central nervous system at the level of motor function and behavior.

5. Davis M.B., et al. Distinct Transcript Isoforms of the Atypical Chemokine Receptor 1 (ACKR1)/Duffy Antigen Receptor for Chemokines (DARC) Gene Are Expressed in Lymphoblasts and Altered Isoform Levels Are Associated with Genetic Ancestry and the Duffy-Null Allele. PLoS One. 2015, 10(10): e0140098. PubMed ID: 26473357
   
   

   This article suggests that people of African ancestry have distinct relative levels of DARC isoforms. The expression of both isoforms in combination with alternate alleles yields multiple Duffy antigens in ancestry groups, depending upon the haplotypes across the gene.

ACKR1 Preparation Options

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Reference

1. Locati M, et al. (2017). Atypical matters in myeloid differentiation. Nature Immunology. 18(7): 711-712.

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