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Conventional and atypical chemokine receptors: different mechanisms of function and common responses

English title Conventional and atypical chemokine receptors: different mechanisms of function and common responses
Applicant Thelen Marcus
Number 140704
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 01.06.2012 - 30.09.2015
Approved amount 277'000.00
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Keywords (5)

CXCR7; CCR2; atypical chemokine receptor; chemokine receptor; B cells

Lay Summary (English)

Lead
Lay summary

When mammals become exposed to pathogens, such as bacteria, yeast or viruses, the organism defend themselves with an protective immune response. A critical step in building this defense is the recruitment of leukocytes from the blood to the site were the pathogen has attacked the host. The main task of the leukocytes is to eliminate the invaders and to launch the generation of antibodies or specific killer cells to vaccinate the host and to protect against future attacks. So called chemotactic cytokines (chemokines) are the critical regulators for this leukocyte traffic.

After pathogen eradication by innate and adaptive immunity, it is mandatory that the immune system returns to its resting state. Excessive activation of the inflammatory response can be deleterious for the host. For this purpose, the balanced formation and scavenging of inflammatory mediators is, next to leukocyte trafficking, most critical for an effective inflammatory response that does not become damaging for the host.

The laboratory recently described CXCR7 as novel scavenger receptor for the chemokine CXCL12. Investigations of the laboratory demonstrated that the receptor does not trigger typical responses induced by chemokines, such as leukocyte migration, but rather removes chemokines by cycling between the surface and endosomal compartments. CXCR7 nevertheless shares the overall structure with other chemokine receptors and is phylogenetically related. Thus, an obvious question is what molecular properties distinguishes the receptor from its functional signaling siblings. To this end we will investigate intracellular signaling mediated by the receptor, focusing on protein phosphorylation, an event that is tightly associated with receptor endocytosis. We will use fluorescently labeled chemokines, that can readily be detected by advanced microscopy to reveal the scavenging activity of CXCR7 in different tissues. 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15
Bachelerie Françoise, Graham Gerard J., Locati Massimo, Locati Massimo, Mantovani Alberto, Mantovani Alberto, Murphy Philip M., Nibbs Robert, Rot Antal, Sozzani Silvano, Sozzani Silvano, Thelen Marcus (2015), An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15, in British Journal of Pharmacology, 172(16), 3945-3949.
Herpes simplex virus enhances chemokine function through modulation of receptor trafficking and oligomerization
Martinez-Martin Nadia, Martinez-Martin Nadia, Viejo-Borbolla Abel, Viejo-Borbolla Abel, Martín Rocío, Blanco Soledad, Benovic Jeffrey L., Thelen Marcus, Alcamí Antonio, Alcamí Antonio (2014), Herpes simplex virus enhances chemokine function through modulation of receptor trafficking and oligomerization, in Nature Communications, 6, 6163.
International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.
Bachelerie Francoise, Ben-Baruch Adit, Burkhardt Amanda M., Combadiere Christophe, Farber Joshua M., Graham Gerard J., Horuk Richard, Sparre-Ulrich Alexander Hovard, Locati Massimo, Luster Andrew D., Mantovani Alberto, Matsushima Kouji, Murphy Philip M., Nibbs Robert, Nomiyama Hisayuki, Power Christine A., Proudfoot Amanda E I, Rosenkilde Mette M., Rot Antal, Sozzani Silvano, Thelen Marcus, Yoshie Osamu, Zlotnik Albert (2014), International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors., in Pharmacological reviews, 66(1), 1-79.
New nomenclature for atypical chemokine receptors
Bachelerie Françoise, Graham Gerard J., Locati Massimo, Mantovani Alberto, Murphy Philip M., Nibbs Robert, Rot Antal, Sozzani Silvano, Sozzani Silvano, Thelen Marcus (2014), New nomenclature for atypical chemokine receptors, in Nature Immunology, 15(3), 207-208.
CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis
Zohar Yaniv, Wildbaum Gizi, Novak Rostislav, Salzman Andrew L., Thelen Marcus, Alon Ronen, Barsheshet Yiftah, Karp Christopher L., Karp Christopher L., Karin Nathan, Karin Nathan (2013), CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis, in Journal of Clinical Investigation, 124(5), 2009-2022.
CXCR7 influences the migration of B cells during maturation
Humpert Marie Luise, Humpert Marie Luise, Pinto Dora, Jarrossay David, Thelen Marcus (2013), CXCR7 influences the migration of B cells during maturation, in European Journal of Immunology, 44(3), 694-705.
CXCR7 prevents excessive CXCL12-mediated downregulation of CXCR4 in migrating cortical interneurons
Abe Philipp, Mueller Wiebke, Schütz Dagmar, MacKay Fabienne, Thelen Marcus, Zhang Penglie, Stumm Ralf (2013), CXCR7 prevents excessive CXCL12-mediated downregulation of CXCR4 in migrating cortical interneurons, in Development (Cambridge), 141(9), 1857-1863.
Expression of the Chemokine Receptor CXCR7 in CXCR4-Expressing Human 143B Osteosarcoma Cells Enhances Lung Metastasis of Intratibial Xenografts in SCID Mice
Brennecke Patrick, Arlt Matthias J. E., Muff Roman, Campanile Carmen, Gvozdenovic Ana, Husmann Knut, Holzwarth Nathalie, Cameroni Elisabetta, Ehrensperger Felix, Thelen Marcus, Born Walter, Fuchs Bruno (2013), Expression of the Chemokine Receptor CXCR7 in CXCR4-Expressing Human 143B Osteosarcoma Cells Enhances Lung Metastasis of Intratibial Xenografts in SCID Mice, in PLOS ONE, 8(9), e74045.
Immune response: Steroids drive dendritic cells
Jarrossay David, Thelen Marcus (2013), Immune response: Steroids drive dendritic cells, in Nature Immunology, 14(5), 424-426.
CCR2 Acts as Scavenger for CCL2 during Monocyte Chemotaxis
Volpe Silvia, Cameroni Elisabetta, Moepps Barbara, Thelen Sylvia, Apuzzo Tiziana, Thelen Marcus (2012), CCR2 Acts as Scavenger for CCL2 during Monocyte Chemotaxis, in PLOS ONE, 7(5), e37208.
Complementary methods provide evidence for the expression of CXCR7 on human B cells
Humpert Marie Luise, Tzouros Manuel, Thelen Sylvia, Bignon Alexandre, Bignon Alexandre, Levoye Angélique, Arenzana-Seisdedos Fernando, Balabanian Karl, Balabanian Karl, Bachelerie Françoise, Bachelerie Françoise, Langen Hanno, Thelen Marcus (2012), Complementary methods provide evidence for the expression of CXCR7 on human B cells, in Proteomics, 12(12), 1938-1948.
Expression of CXCL12 receptors in B cells from Mexican Mestizos patients with systemic lupus erythematosus
Biajoux Vincent, Biajoux Vincent, Bignon Alexandre, Bignon Alexandre, Freitas Christelle, Freitas Christelle, Martinez Valérie, Martinez Valérie, Martinez Valérie, Thelen Marcus, Lima Guadalupe, Jakez-Ocampo Juan, Emilie Dominique, Emilie Dominique, Emilie Dominique, Llorente Luis, Balabanian Karl, Balabanian Karl (2012), Expression of CXCL12 receptors in B cells from Mexican Mestizos patients with systemic lupus erythematosus, in Journal of Translational Medicine, 10(1), 251.
The biochemistry and biology of the atypical chemokine receptors
Graham G. J., Locati M., Mantovani A., Rot A., Thelen M. (2012), The biochemistry and biology of the atypical chemokine receptors, in IMMUNOLOGY LETTERS, 145(1-2), 30-38.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
University of Minas Gerais, seminar Individual talk ACKR3 (CXCR7) role in B cells 31.08.2015 Belo Horizonte, Brazil Thelen Marcus;
University of Erlangen, seminar Individual talk ACKR3 (CXCR7): role in B cell responses 07.07.2015 Erlangen, Germany Thelen Marcus;
Midwinter Conference Advances in immunology Poster Functional ACKR3 expression in the B cell compartment 17.01.2015 Seefeld in Tirol, Austria Radice Egle;
5th EADV dermatology meeting in Ticino Talk given at a conference The chemokine decoy ACKR3 in health and disease 04.12.2014 Bellinzona, Switzerland Thelen Marcus;
University of Padova Talk given at a conference The chemokine system in cancer 21.11.2014 Padova, Italy Thelen Marcus;
Imaging the Immune System Poster ACKR3 (CXCR7) in the B celkl compartment and its contribution for a long lasting humoral response 23.10.2014 Milan, Italy Radice Egle;
Corte Franca Summit Talk given at a conference CXCR7 (ACKR3) in B cells 25.09.2014 Corte Franca, Italy Thelen Marcus;
Vanderbilt University Talk given at a conference CXCR7 (ACKR3) in B cells 04.08.2014 Nashville, United States of America Thelen Marcus;
Gordon Research Conference Chemotactic Cytokines Talk given at a conference Regulation of Chemokine Function / Discussion leader - introduction 27.07.2014 West Dover, United States of America Thelen Marcus;
Cytomeet University of Bern Talk given at a conference Cell migration mediated by atipical chemokine receptors 14.01.2014 Bern, Switzerland Thelen Marcus;
Actelion Pharmaceuticals Talk given at a conference Cell migration governed by the atypical chemokine receptor ACKR3 10.01.2014 Allschwil, Switzerland Thelen Marcus;
University of Torino Talk given at a conference Why B cells (not) respond to CXCL12? 18.11.2013 Torino, Italy Thelen Marcus;
University of Brescia Talk given at a conference Why B cells (not) respond to CXCL12? 31.10.2013 Brescia, Italy Thelen Marcus;
University of Iowa Talk given at a conference Why B cells (not) respond to CXCL12? 23.09.2013 Iowa City, United States of America Thelen Marcus;
ESF-EMBO Symposium - B Cells From Bedside To Bench And Back Again Talk given at a conference Functional role of CXCR7 expression on late germinal center B cells 02.09.2013 Pultusk, Poland Humpert Marie-Luise;
8th ENII Summer School in Advanced Immunology Poster Role of CXCR7 Expression on Late Germinal Center B Cells 27.05.2013 Porto Conte, Alghero, Sardinia, Italy Humpert Marie-Luise;
University of Ghent Talk given at a conference Why B cells (not) respond to CXCL12? 17.04.2013 Ghent, Belgium Thelen Marcus;
Keyston Symposium on molecular and cellular biology Talk given at a conference Functional Role of CXCR7 Expression on Late Germinal Center B Cells 10.02.2013 Keystone, Colorado, United States of America Humpert Marie-Luise;
GCB Students' Symposium 2013 Talk given at a conference Molecular mechanisms of CXCR7 sorting and potential signaling properties 30.01.2013 Bern, Switzerland Humpert Marie-Luise;
Istituto Clinico Humanitas Talk given at a conference Why B cells (not) respond to CXCL12? 14.01.2013 Milan, Italy Thelen Marcus;
Multiple faces of the chemokine CXCL12 Talk given at a conference Why B cells (not) respond to CXCL12? 12.12.2012 Paris, France Thelen Marcus;
4th EADV dermatological meeting in Ticino Talk given at a conference News from CXCR7 08.11.2012 Bellinzona, Switzerland Thelen Marcus;
University of Zurich, seminar Talk given at a conference Atypical Chemokine receptors: CXCR7 Expression and Function 26.10.2012 Zurich, Switzerland Thelen Marcus;
Horizon in molecular biology, International PhD student symposium Poster molecular mechanisms of CXCR7 sorting and potential signaling properties 08.10.2012 Göttingen, Germany Humpert Marie-Luise;


Associated projects

Number Title Start Funding scheme
163336 The Atypical Chemokine Receptor ACKR3: Function in vivo in Immune Responses and Coupling to Signal Transduction Pathways 01.10.2015 Project funding
163336 The Atypical Chemokine Receptor ACKR3: Function in vivo in Immune Responses and Coupling to Signal Transduction Pathways 01.10.2015 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
112214 Chemokine receptors and signal transduction pathways in leukocytes 01.06.2006 Project funding
157699 Acquisition of a 600MHz solution NMR spectrometer 01.10.2015 R'EQUIP
145038 Acquisition of a 2-Photon microscope for intravital analysis 01.12.2012 R'EQUIP

Abstract

Cell migration is intrinsic to any higher organisms. Starting early in development cell migration can be observed during all ages. The mechanisms of cell migration can be seen from two edges: the attracting cues and the molecular mechanism allowing a single cell to move. The chemokine system has emerged as a major regulator of these processes and is best studies for its involvement in leukocyte trafficking. The system is comprised on one side by the chemokines, small 8-10 kD peptides, that are ubiquitously produced and form chemotactic gradients by binding to cell surfaces or matrix proteins, on the other side are the chemokine receptors, all structurally closely related to rhodopsin-like G-protein coupled receptors. Conventional chemokine receptors are selectively expressed on different leukocytes (and also non-hematopoietic cells) and respond to distinct chemokines activating intracellular signaling cascades via pertussis-toxin sensitive Gi-proteins. Recently a subset of chemokine receptors has emerged, which do not trigger typical intracellular signaling, but have in common the ability to internalize, degrade, or transport their ligands. This function enables them to modify gradients and create functional chemokine patterns in tissues. A member of the atypical chemokine receptors is CXCR7, a receptor that was deorphanized in our laboratory as second receptor for the chemokine CXCL12. Is critical involvement in the development of mice is manifested by the fact that targeted deletion is lethal. CXCR7 has received much attention in cancer studies, being expressed on many tumors, but compelling evidence exist showing its role in leukocyte traffic, e.g. for invasion of leukocytes into the CNS. Despite that several studies from different laboratories describe CXCR7 expression in leukocytes, one laboratory has claimed that the receptor in not expressed in leukocytes. Recently, we provided compelling evidence showing the expression of the receptor in B cells (submitted manuscript) . Thus, we propose her to further investigate the function of CXCR7 in the B cell compartment. Our initial studies (2006) pointed at an important role of CXCR7 in B cell differentiation to plasma cells. Based on preliminary data we hypothesize that CXCR7 expression on plasmablast is critical for developing long lasting immune responses. The well accepted scavenging activity of CXCR7 is associated with trafficking of the receptor though endosomal pathways deploying the bound CXCL12 for degradation while recycling to the cell surface. Using fluorescence microscopy in the first place we propose to investigate the endocytic route of CXCR7. We suggest to search for structural determinants that regulate the pathway and are responsible for the scavenging activity and are not comprised in the sequence of conventional chemokine receptors. The data will reveal mechanisms of receptor recycling, which is important for the understanding of the proposed role of the receptor in regulating cell trafficking.Chemotaxis of leukocytes mediated by conventional receptors. For efficient migration, receptor responsiveness must be maintained whilst the cells crawl on cell surfaces or on matrices along the attracting gradient towards increasing concentrations of agonist. On the other hand agonist-induced desensitization and internalization is a general paradigm for chemokine receptors which is inconsistent with the prolonged migratory capacity. Using time-lapse video microscopy and fluorescent labeled receptors and chemokines we propose to study the localization and endocytic behavior of the chemotaxis-mediating receptors. Using genetically encoded calcium indicators we will test receptor responsiveness and potential desensitization during migration.With present project we give a new direction to our long standing endeavor to elucidate the role of chemokine receptors in regulating leukocyte trafficking. Investigating the properties of conventional and atypical receptors in shall unveil common and distinct mechanisms in this process.
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