Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells

The Duffy antigen receptor for chemokines (DARC) shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. How...

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Bibliographic Details
Published in:PloS one 2011-12, Vol.6 (12), p.e29624-e29624
Main Authors: Zhao, Yani, Mangalmurti, Nilam S, Xiong, Zeyu, Prakash, Bharat, Guo, Fengli, Stolz, Donna B, Lee, Janet S
Format: Article
Language:English
Subjects:
Affinity
Amiloride
Amiloride - pharmacology
Antigens
Biology
Caveolin
Caveolin-1
Chemokines
Chemokines - metabolism
Cholesterol
Clathrin
Critical care
CXC chemokines
Cytochalasin D
Duffy antigen
Duffy Blood-Group System - immunology
Dynamin
Endocytosis
Endothelial cells
Endothelium
Endothelium - cytology
Endothelium - metabolism
Erythrocytes
Flow Cytometry
Granulocytes
Humans
Inflammation
Inhibition
Internalization
Ligands
Localization
Medicine
Microscopy, Electron, Transmission
Neutrophils
Nitric oxide
Physiology
Pinocytosis
Platelet-derived growth factor
Protein kinase C
Protein Kinase C - metabolism
Proteins
Receptors, Antigen - immunology
Receptors, Antigen - metabolism
Recruitment
Scaffolding
Trends
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Summary:The Duffy antigen receptor for chemokines (DARC) shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear. We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated (125)I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. (125)I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression.(125)I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF) enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells. These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0029624