GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis

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Significance

G protein–coupled receptors (GPCRs) are important regulators of cellular and biological functions and are primary targets of therapeutic drugs. About 100 mammalian GPCRs are still considered orphan receptors because they lack a known endogenous ligand. We report the deorphanization of GPR182, which is expressed in endothelial cells of the microvasculature. We show that GPR182 is an atypical chemokine receptor, which binds CXCL10, 12, and 13. However, binding does not induce downstream signaling. Consistent with a scavenging function of GPR182, mice lacking GPR182 have increased plasma levels of chemokines. In line with the crucial role of CXCL12 in hematopoietic stem cell homeostasis, we found that loss of GPR182 results in increased egress of hematopoietic stem cells from the bone marrow.

Abstract

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 G _q- and G _i-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.

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Trends in GPCR drug discovery: new agents, targets and indications

Alexander S Hauser, Misty Attwood, Mathias Rask-Andersen … (2017)

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, largely due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report the first analysis of all GPCR drugs and agents in clinical trials. This reveals the current trends across molecule types, drug targets and therapeutic indications, including showing that 481 drugs (~34% of all drugs approved by the FDA) act at 107 unique GPCR targets. Approximately 320 agents are currently in clinical trials, of which ~36% target 64 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has grown. The major disease indications for GPCR modulators show a shift towards diabetes, obesity, and Alzheimer’s disease, while other central nervous system disorders remain highly represented. The 227 (57%) non-olfactory GPCRs that are yet to be explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

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Chemokines and chemokine receptors: positioning cells for host defense and immunity.

Jason Griffith, Caroline L. Sokol, Andrew D. Luster (2014)

Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein-coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.

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A guide to chemokines and their receptors

Catherine Hughes, Robert Nibbs (2018)

The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein‐coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behavior, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many nonleukocytic cell types. Chemokines are profoundly affected by post‐translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical ‘atypical’ chemokine receptors that regulate chemokine localization and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarizes the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focusing particularly on their ability to direct leukocyte migration.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 27 April 2021

Publication date (Electronic): 19 April 2021

Publication date PMC-release: 19 April 2021

Volume: 118

Issue: 17

Electronic Location Identifier: e2021596118

Affiliations

[1] ^aDepartment of Pharmacology, Max Planck Institute for Heart and Lung Research , Bad Nauheim, 61231, Germany;

[2] ^bDepartment of Medicine, Hematology/Oncology, Goethe University Hospital , 60590 Frankfurt, Germany;

[3] ^cDepartment of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland;

[4] ^dDepartment of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine , 48149 Münster, Germany;

[5] ^eGerman Cancer Consortium and German Cancer Research Center , Heidelberg, 69120, Germany;

[6] ^fFrankfurt Cancer Institute , 60590 Frankfurt, Germany;

[7] ^gCardio-Pulmonary Institute , 60590 Frankfurt, Germany;

[8] ^hGerman Centre for Cardiovascular Research , Rhine-Main site, Frankfurt and Bad Nauheim, 60590, Germany;

[9] ⁱCentre for Molecular Medicine, Medical Faculty, Goethe University Frankfurt , 60590 Frankfurt, Germany

Author notes

²To whom correspondence may be addressed. Email: remy.bonnavion@ 123456mpi-bn.mpg.de or Stefan.Offermanns@ 123456mpi-bn.mpg.de .

Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute, Durham, NC, and approved March 8, 2021 (received for review October 15, 2020)

Author contributions: R.B., M.A.R., and S.O. designed research; A.L.M., R.B., W.Y., M.W.A., S.R., Y.Z., Y.J., K.A.R., H.-W.J., K.K.S., H.C., X.C., B.S., and T.S. performed research; R.A. and T.S. contributed new reagents/analytic tools; A.L.M., R.B., W.Y., M.W.A., S.R., Y.Z., and S.O. analyzed data; A.L.M., R.B., and S.O. wrote the paper; and R.A. discussed data.

¹A.L.M. and R.B. contributed equally to this work.