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    G protein-coupled receptor 182 (GPR182) has been shown to be expressed in endothelial cells; however, its ligand and physiological role has remained elusive. We found GPR182 to be expressed in microvascular and lymphatic endothelial cells of most organs and to bind with nanomolar affinity the chemokines CXCL10, CXCL12, and CXCL13. In contrast to conventional chemokine receptors, binding of chemokines to GPR182 did not induce typical downstream signaling processes, including Gq- and Gi-mediated signaling or β-arrestin recruitment. GPR182 showed relatively high constitutive activity in regard to β-arrestin recruitment and rapidly internalized in a ligand-independent manner. In constitutive GPR182-deficient mice, as well as after induced endothelium-specific loss of GPR182, we found significant increases in the plasma levels of CXCL10, CXCL12, and CXCL13. Global and induced endothelium-specific GPR182-deficient mice showed a significant decrease in hematopoietic stem cells in the bone marrow as well as increased colony-forming units of hematopoietic progenitors in the blood and the spleen. Our data show that GPR182 is a new atypical chemokine receptor for CXCL10, CXCL12, and CXCL13, which is involved in the regulation of hematopoietic stem cell homeostasis. Copyright © 2021 the Author(s). Published by PNAS.

    Citation

    Alan Le Mercier, Remy Bonnavion, Weijia Yu, Mohamad Wessam Alnouri, Sophie Ramas, Yang Zhang, Yannick Jäger, Kenneth Anthony Roquid, Hyun-Woo Jeong, Kishor Kumar Sivaraj, Haaglim Cho, Xinyi Chen, Boris Strilic, Tjeerd Sijmonsma, Ralf Adams, Timm Schroeder, Michael A Rieger, Stefan Offermanns. GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2021 Apr 27;118(17)

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    PMID: 33875597

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