TY - JOUR
T1 - GPR182 is a broadly scavenging atypical chemokine receptor influencing T-independent immunity
AU - Melgrati, Serena
AU - Gerken, Oliver J.
AU - Artinger, Marc
AU - Radice, Egle
AU - Szpakowska, Martyna
AU - Chevigné, Andy
AU - D’Uonnolo, Giulia
AU - Antonello, Paola
AU - Thelen, Sylvia
AU - Pelczar, Pawel
AU - Legler, Daniel F.
AU - Thelen, Marcus
N1 - Funding Information:
The study was supported by grants from Swiss National Science Foundation (Sinergia CRSII3_160719 (DL & MT) and 310030_182727 (MT)), the Novartis Foundation for medical-biological Research (#17B098 (MT)), the Fondazione Fidinam, Lugano (MT), the Helmut Horten Foundation and by the Luxembourg National Research Fund (INTER/FNRS grants 20/15084569) and F.R.S.-FNRS-Télévie (grants 7.8504.20, 7.4502.21 and 7.8508.22) AC & MS)). Acknowledgments
Publisher Copyright:
Copyright © 2023 Melgrati, Gerken, Artinger, Radice, Szpakowska, Chevigné, D’Uonnolo, Antonello, Thelen, Pelczar, Legler and Thelen.
PY - 2023/7/24
Y1 - 2023/7/24
N2 - Immune responses highly depend on the effective trafficking of immune cells into and within secondary lymphoid organs (SLOs). Atypical chemokine receptors (ACKRs) scavenge chemokines to eliminate them from the extracellular space, thereby generating gradients that guide leukocytes. In contrast to canonical chemokine receptors, ACKRs do not induce classical intracellular signaling that results in cell migration. Recently, the closest relative of ACKR3, GPR182, has been partially deorphanized as a potential novel ACKR. We confirm and extend previous studies by identifying further ligands that classify GPR182 as a broadly scavenging chemokine receptor. We validate the “atypical” nature of the receptor, wherein canonical G-protein-dependent intracellular signaling is not activated following ligand stimulation. However, β-arrestins are required for ligand-independent internalization and chemokine scavenging whereas the C-terminus is in part dispensable. In the absence of GPR182 in vivo, we observed elevated chemokine levels in the serum but also in SLO interstitium. We also reveal that CXCL13 and CCL28, which do not bind any other ACKR, are bound and efficiently scavenged by GPR182. Moreover, we found a cooperative relationship between GPR182 and ACKR3 in regulating serum CXCL12 levels, and between GPR182 and ACKR4 in controlling CCL20 levels. Furthermore, we unveil a new phenotype in GPR182-KO mice, in which we observed a reduced marginal zone (MZ), both in size and in cellularity, and thus in the T-independent antibody response. Taken together, we and others have unveiled a novel, broadly scavenging chemokine receptor, which we propose should be named ACKR5.
AB - Immune responses highly depend on the effective trafficking of immune cells into and within secondary lymphoid organs (SLOs). Atypical chemokine receptors (ACKRs) scavenge chemokines to eliminate them from the extracellular space, thereby generating gradients that guide leukocytes. In contrast to canonical chemokine receptors, ACKRs do not induce classical intracellular signaling that results in cell migration. Recently, the closest relative of ACKR3, GPR182, has been partially deorphanized as a potential novel ACKR. We confirm and extend previous studies by identifying further ligands that classify GPR182 as a broadly scavenging chemokine receptor. We validate the “atypical” nature of the receptor, wherein canonical G-protein-dependent intracellular signaling is not activated following ligand stimulation. However, β-arrestins are required for ligand-independent internalization and chemokine scavenging whereas the C-terminus is in part dispensable. In the absence of GPR182 in vivo, we observed elevated chemokine levels in the serum but also in SLO interstitium. We also reveal that CXCL13 and CCL28, which do not bind any other ACKR, are bound and efficiently scavenged by GPR182. Moreover, we found a cooperative relationship between GPR182 and ACKR3 in regulating serum CXCL12 levels, and between GPR182 and ACKR4 in controlling CCL20 levels. Furthermore, we unveil a new phenotype in GPR182-KO mice, in which we observed a reduced marginal zone (MZ), both in size and in cellularity, and thus in the T-independent antibody response. Taken together, we and others have unveiled a novel, broadly scavenging chemokine receptor, which we propose should be named ACKR5.
KW - atypical chemokine receptor
KW - chemokine
KW - GPR182
KW - marginal zone
KW - signal transduction
UR - http://www.scopus.com/inward/record.url?scp=85167352509&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37554323
U2 - 10.3389/fimmu.2023.1242531
DO - 10.3389/fimmu.2023.1242531
M3 - Article
C2 - 37554323
SN - 1664-3224
VL - 14
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 1242531
ER -