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The Atypical Chemokine Receptor ACKR3: Function in vivo in Immune Responses and Coupling to Signal Transduction Pathways

English title The Atypical Chemokine Receptor ACKR3: Function in vivo in Immune Responses and Coupling to Signal Transduction Pathways
Applicant Thelen Marcus
Number 163336
Funding scheme Project funding
Research institution Istituto di ricerca in biomedicina (IRB) Facoltà di scienze biomedice
Institution of higher education Università della Svizzera italiana - USI
Main discipline Cellular Biology, Cytology
Start/End 01.10.2015 - 30.09.2018
Approved amount 291'000.00
Show all

All Disciplines (2)

Discipline
Cellular Biology, Cytology
Molecular Biology

Keywords (7)

Biased signaling; Immune response; CXCR4; Chemokine; B cell; ACKR3; Proximity labeling

Lay Summary (German)

Lead
Der atypische Chemokinrezeptor ACKR3 kann durch seine Eigenschaft das Chemokin CXCL12 zu eliminieren die Migration und Positionierung von Zellen beeinflussen, die den typischen Rezeptor für CXCL12 CXCR4 exprimieren. Unsere Forschung hat gezeigt, dass ACKR3 eine Schlüsselfunktion bei der Bildung der protektiven humoralen Immunität spielen könnte. In diesem Projekt sollen diese Beobachtungen mit in vivo Modellen bestätigt werden und der Mechanismus der ACKR3 vermittelten Elimination von Chemokinen untersucht werden.
Lay summary

Inhalt und Ziele des Forschungsprojekts

ACKR3 ermöglicht vermutlich durch Neutralisierung von CXCL12 die Auswanderung von Plasmablasten aus den Keimzentren der B-Zellfollikel. Inhibition des ACKR3 verhindert die Emigration und die anschliessende Einnistung der Zellen im Knochenmark. In Modellen, bei welchen die Expression des ACKR3 zu verschiedenen Zeitpunkten der B-Zellentwicklung genetisch unterbunden wird, soll diese Funktion des Rezeptors eindeutig belegen.

Kürzlich ist es uns gelungen durch den Einsatz einer Reportermaus, die anstelle eines Allels des ACKR3 ein fluoreszierendes Protein im Genom trägt, zu zeigen, dass 50% B Zellen der Marginalzone in der Milz ACKR3 exprimieren. Es ist ein Ziel des Projektes diesen neuen Befund zweier unterschiedlicher Zellpopulationen der Marginalzone zu untersuchen.

Im Gegensatz zu CXCR4 koppelt ACKR3 nicht an G-proteine, vermutlich interagieren die Rezeptoren aber auch mit verschiedenen intrazellulären Proteinen. Dies soll mit der APEX2 Technologie untersucht werden.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt befasst sich mit Grundlagenforschung. Um ein besseres Verständnis der Immunantwort zu erhalten, ist es notwendig mit geeigneten Modellen die Funktion des ACKR3 zu erforschen.

Direct link to Lay Summary Last update: 23.10.2015

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis
Girbl Tamara, Lenn Tchern, Perez Lorena, Rolas Loïc, Barkaway Anna, Thiriot Aude, del Fresno Carlos, Lynam Eleanor, Hub Elin, Thelen Marcus, Graham Gerard, Alon Ronen, Sancho David, von Andrian Ulrich H., Voisin Mathieu-Benoit, Rot Antal, Nourshargh Sussan (2018), Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis, in Immunity, 30433.
Redox-Mediated Mechanisms Fuel Monocyte Responses to CXCL12/HMGB1 in Active Rheumatoid Arthritis
Cecchinato Valentina, D'Agostino Gianluca, Raeli Lorenzo, Nerviani Alessandra, Schiraldi Milena, Danelon Gabriela, Manzo Antonio, Thelen Marcus, Ciurea Adrian, Bianchi Marco E., Rubartelli Anna, Pitzalis Costantino, Uguccioni Mariagrazia (2018), Redox-Mediated Mechanisms Fuel Monocyte Responses to CXCL12/HMGB1 in Active Rheumatoid Arthritis, in Frontiers in Immunology, 9, 2118.
Membrane lipid environment: Potential modulation of chemokine receptor function
Thelen Marcus, Legler Daniel F. (2018), Membrane lipid environment: Potential modulation of chemokine receptor function, in Cytokine, 109, 72-75.
New insights in chemokine signaling
Legler Daniel F., Thelen Marcus (2018), New insights in chemokine signaling, in F1000Research, 95-95.
ACKR3 expression on diffuse large B cell lymphoma is required for tumor spreading and tissue infiltration
Puddinu Viola, Casella Sabrina, Radice Egle, Thelen Sylvia, Dirnhofer Stefan, Bertoni Francesco, Thelen Marcus (2017), ACKR3 expression on diffuse large B cell lymphoma is required for tumor spreading and tissue infiltration, in Oncotarget, (49), 85068.
The Atypical Receptor CCRL2 (C-C Chemokine Receptor-Like 2) Does Not Act As a Decoy Receptor in Endothelial Cells
Mazzotti Chiara, Gagliostro Vincenzo, Bosisio Daniela, Del Prete Annalisa, Tiberio Laura, Thelen Marcus, Sozzani Silvano (2017), The Atypical Receptor CCRL2 (C-C Chemokine Receptor-Like 2) Does Not Act As a Decoy Receptor in Endothelial Cells, in Frontiers in Immunology, 8, 1233.

Collaboration

Group / person Country
Types of collaboration
Santiago F. González / Institute for Research in Biomedicine Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Cornelia Halin / ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Bernd Wollscheid / Institute of Molecular Systems Biology / ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Antol Rot / Queen Mary University London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Daniel Legler / BITg / Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Bernard Moser / University of Cardiff Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Silvano Sozzani / University of Brescia Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Barbara Moepps / University of Ulm / Germany Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Cell Migration Retreat Talk given at a conference The APEX2 system: an approach for the identification of ACKR3 interactome 06.09.2018 Gerzensee, Switzerland Casella Sabrina;
ONCORNET Talk given at a conference The role of ACKR3 in health and disease 30.08.2018 Amsterdam, Netherlands Thelen Marcus;
Gordon Research Conference, Chemotactic Cytokines Talk given at a conference The APEX2 system: an approach for the identification of ACKR3 interactome 03.06.2018 Newry, United States of America Casella Sabrina;
Gordon Research Conference Poster Role of ACKR3 in leukocyte migration and the microarchitecture of secondary lymphoid organs 03.06.2018 Newry, United States of America Thelen Marcus;
Gordon Research Conference, Chemotactic Cytokines Poster The APEX2 system: a new approach for the identification of CXCR4 and ACKR3 interacting proteins 03.06.2018 Newry, United States of America Thelen Marcus; Casella Sabrina;
Gordon Research Conference, Chemotactic Cytokines Poster Marginal zone formation requires ACKR3 expression on B cells 03.06.2018 Newry, United States of America Thelen Marcus;
SFB1192 Retreat Liguria Talk given at a conference ACKR3 (CXCR7) and the Hamburg connection 16.05.2018 Imperia, Switzerland Thelen Marcus;
Annual Swiss Proteomics Meeting Talk given at a conference The APEX system: an approach for the identification of ACKR3 interactome 19.04.2018 Montreux, Switzerland Casella Sabrina;
University of Lausanne Individual talk The atypical chemokine receptor 3 expression and function 14.02.2018 Lausanne, Switzerland Thelen Marcus;
GCB Symposium Poster Role of ACKR3 in leukocyte migration and the microarchitecture of secondary lymphoid organs 01.02.2018 Bern, Switzerland Thelen Marcus;
University of Padova Individual talk The Chemokine System in cancer 23.11.2017 23.11.2017, Italy Thelen Marcus;
University of Brescia Individual talk Chemokine orchestrate cell migration and more 21.11.2017 Brescia, Italy Thelen Marcus;
9th European Academy of Dermatology and Venerology Talk given at a conference Atypical chemokine receptors in disease 26.10.2017 Bellinzona, Switzerland Thelen Marcus;
FEBS Immunology Summer school Poster The APEX system: a new approach for the identification of CXCR4 and ACKR3 interacting proteins 23.09.2017 Hvar, Croatia Thelen Marcus; Casella Sabrina;
ECMC2017 Cardiff Poster Role of ACKR3 in leukocyte migration and the microarchitecture of secondary lymphoid organs 06.09.2017 Cardiff, Great Britain and Northern Ireland Thelen Marcus;
2nd European Chemokine and Cell Migration Conference Talk given at a conference Vice Chair 06.09.2017 Cardiff, Great Britain and Northern Ireland Thelen Marcus;
STIMM University of Zurich Individual talk The Atypical Chemokine Receptor ACKR3 05.07.2017 Zurich, Switzerland Thelen Marcus;
Annual Meeting of the Swiss Society for Allergology and Immunology. St. Gallen Poster ACKR3 in leukocyte migration and the microarchitecture of secondary lymphoid organs 01.06.2017 St. Gallen, Switzerland Thelen Marcus;
Kantonsspital St. Gallen Individual talk Atypical Chemokine Receptors 28.04.2017 St. Gallen, Switzerland Thelen Marcus;
GCB Symposium Poster Role of ACKR3 in leukocyte migration and the microarchitecture of secondary lymphoid organs 02.02.2017 Bern, Switzerland Thelen Marcus;
GCB Symposium Poster The APEX system: a new approach for the identification of CXCR4 and ACKR3 interacting proteins 02.02.2017 Bern, Switzerland Casella Sabrina; Thelen Marcus;
26th Cytomeet Talk given at a conference The role of the atypical chemokine receptor ACKR3 in leukocytes 24.01.2017 Bern, Switzerland Thelen Marcus;
8th European Academy of Dermatology and Venerology Talk given at a conference The atypical chemokine receptor ACKR3 in immune responses 01.12.2016 Bellinzona, Switzerland Thelen Marcus;
University of Padova Individual talk The Chemokine System in cancer 24.11.2016 Padova, Italy Thelen Marcus;
Cell Migration Retreat Poster Role of ACKR3 in leukocyte migration and the microarchitecture of secondary lymphoid organs 27.10.2016 Gunten, Switzerland Thelen Marcus;
Cell Migration Retreat Poster The APEX system: a new approach for the identification of CXCR4 and ACKR3 interacting proteins 27.10.2016 Gunten, Switzerland Thelen Marcus; Casella Sabrina;
ETH Zurich Individual talk Cell Migration is Controlled by Typical and Atypical Chemokine Receptors 28.09.2016 Zurich, Switzerland Thelen Marcus;
Gordon Research Conference, Chemotactic Cytokines Talk given at a conference Scavenging activity of ACKR3 in health and disease 03.06.2016 Newry, United States of America Thelen Marcus;
Gordon Research Conference, Chemotactic Cytokines Talk given at a conference ACKR3: A marker for B cell populations 29.05.2016 Girona, Spain Thelen Marcus;
Gordon Research Conference Poster Role of ACKR3 in leukocyte migration and the microarchitecture of secondary lymphoid organs 29.05.2016 Girona, Spain Thelen Marcus;
Gordon Research Conference, Chemotactic Cytokines Poster The APEX2 system: a new approach for the identification of CXCR4 and ACKR3 interacting proteins 29.05.2016 Girona, Spain Casella Sabrina; Thelen Marcus;
Gordon Research Conference, Chemotactic Cytokines Talk given at a conference Mechanisms of Immune System Development and Homeostasis 29.05.2016 Girona, Spain Thelen Marcus;
Gordon Research Conference, Chemotactic Cytokines Poster Functional ACKR3 expression in the B cell compartment 28.05.2016 Girona, Spain Thelen Marcus;
GCB symposium 2016 Poster Functional ACKR3 expression in the B cell compartment 04.01.2016 Bern, Switzerland Thelen Marcus;
University di Padova Individual talk The Chemokine System 27.11.2015 Padova, Italy Thelen Marcus;
7th European Academy of Dermatology and Venerology Talk given at a conference ACKR3 expression on B cells 26.11.2015 Bellinzona, Switzerland Thelen Marcus;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions 50 anni di scienza e gioventù Italian-speaking Switzerland 2017
Talks/events/exhibitions Settimana Tecnologica Liceo Bellinzona Italian-speaking Switzerland 2017

Associated projects

Number Title Start Funding scheme
140704 Conventional and atypical chemokine receptors: different mechanisms of function and common responses 01.06.2012 Project funding
140704 Conventional and atypical chemokine receptors: different mechanisms of function and common responses 01.06.2012 Project funding
182727 Function of ACKR3 in immune cell trafficking in lymphoid organs 01.10.2018 Project funding
160719 Interplay of classical and atypical chemokine receptors in immune cell trafficking and dynamic microarchitecture of the secondary lymphoid organs 01.11.2015 Sinergia
160612 First European Chemokine and Cell Migration Conference (ECMC2015) 01.06.2015 Scientific Conferences
182727 Function of ACKR3 in immune cell trafficking in lymphoid organs 01.10.2018 Project funding

Abstract

In jawed vertebrates throughout development cells migrate along predefined cues to find their destination. In adults most prominent is the continuous movement of immune cells engaged in surveillance and defense of the host. Some tumors have adopted the migratory scheme to escape immune reactions and to spread in metastasis. The chemokine system is known as essential regulator in directing cell migration, where locally produced chemokines form patterns on which cells can migrate through the activation of G-protein coupled chemokine receptors. However, the maintenance of spatial gradients requires the presence of sinks in apposition to the source of attractant. Recently grouped separately and renamed as atypical chemokine receptors, the ACKRs define a group of structurally related receptors for chemokines which mainly act as sinks and therefore support their function in orchestrating cell migration.ACKR3 binds and scavenges the chemokines CXCL12 and CXCL11. Several reports indicate that the receptor contributes to the overall activity of the CXCR4, the chemokine receptor for CXCL12. Its prominent mRNA expression levels in B cells subsets has prompted us to investigate its role in immune responses. We have recently performed in vitro studies showing that ACKR3 is transiently upregulated in plasmablasts during B cell maturation and that the expression is required to license the cells to egress from CXCL12 rich germinal centers. Preliminary data from in vivo studies using pharmacological inhibitors of ACKR3 point in the direction that ACKR3 is required for the prolonged generation of vaccine directed IgG. The finding is consistent with production of IgG from bone marrow resident plasma blasts, which appear absent after inhibition of ACKR3. We intend now to confirm the observations in vivo using appropriate mouse models where conditional ACKR3fl/fl is selectively deleted in the B cell compartment (CD19cre) or in maturing plasmablast (BLIMP-1cre and IgHg1cre). The data shall reveal whether therapeutic inhibition of ACKR3 can be used to suppress undesired immune responses.Using a ACKR3 reporter mouse with an allele of the receptor replaced with green fluorescent protein (GFP) showed a marked expression in marginal zone B (MZB) cells consistent with the reported high mRNA levels. FACS analysis of MZBs surprisingly unveiled that only about 50% of the cells express GFP. The two populations are well separated and we have used these criteria to sort the cells and extracted mRNA for transcriptome analysis. Part of the proposal is to functionally characterize the two populations.ACKR3 like all atypical chemokine receptors does not couple to heterotrimeric G-protein, but can recruit arrestin in response to ligand binding. Although the receptor displays ligand independent cycling addition of chemokine enhances the intracellular trafficking. CXCR4, which couples to Gi-proteins, also binds arrestin and can presumably activate downstream signaling pathways. It was proposed that the equilibrium between G-protein and arrestin-dependent signaling pathways can be modulated by ligands as well as cellular components, a process called biased signaling. We propose here to analyze the receptor proteome of ACKR3 and CXCR4 by APEX2 proximity labeling. Peptides of affinity purified proteins from receptor proteomes obtained under different (biased) stimulatory conditions will be analyzed by mass spectrometry (B. Wollscheid, ETHZ). Quantitative comparison shall provide insight into intracellular signaling networks downstream of ACKR3 and CXCR4. We hope to find markers of biased signaling cascades that may be later used to specifically target the pathways in therapeutic settings.
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