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Impact of Synergy-inducing Molecules on Chemokine Activities

English title Impact of Synergy-inducing Molecules on Chemokine Activities
Applicant Uguccioni Mariagrazia
Number 143718
Funding scheme Project funding (Div. I-III)
Research institution Istituto di Ricerca in Biomedicina (IRB)
Institution of higher education Università della Svizzera italiana - USI
Main discipline Immunology, Immunopathology
Start/End 01.01.2013 - 31.03.2016
Approved amount 439'975.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (3)

Chemokines; Cell trafficking; Inflammation

Lay Summary (Italian)

Lead
Le molecole che controllano il traffico leucocitario sono dei target terapeutici per le malattie infiammatorie
Lay summary

Le chemochine sono proteine ??secrete nello spazio extracellulare che regolano in modo specifico la migrazione cellulare. Gli effetti delle chemochine sono mediati da recettori selettivi presenti sulla superficie dei diversi tipi di globuli bianchi. La conseguente diversità combinatoria in risposta alle chemochine garantisce la corretta distribuzione tissutale delle sottopopolazioni in condizioni normali e infiammatorie / patologiche. Una vasta gamma di studi, volti a capire quali chemochine sono prodotte in circostanze specifiche, ha rivelato che varie chemochine possono essere prodotte contemporaneamente nei tessuti in cui migrano i leucociti. Questo rende il sistema delle chemochine un buon target di terapia, e ha aumentato la ricerca, da parte delle aziende farmaceutiche, di antagonisti delle chemochine. Pur comprendendo bene gli effetti delle singole chemochine, molto meno si conosceva circa le potenziali conseguenze sulla migrazione cellulare, dell'espressione concomitante di più chemochine o di diverse molecole infiammatorie. Il nostro gruppo ha rivelato l'esistenza di caratteristiche aggiuntive delle chemochine: queste molecole possono antagonizzare o aumentare l'attività di altre chemochine. Non vi è più dubbio che queste attività sono cruciali nella fase precoce di infiammazione, mentre lo studio del ruolo delle chemochine nel microambiente tumorale, e di altre molecole infiammatorie, come le allarmine, rilasciate nei tessuti, è ancora agli albori.

La comprensione dei meccanismi che regolano l'attività delle chemochine renderebbe così possibile lo sviluppo di nuove terapie per le malattie infiammatorie, basate su antagonisti specifici con elevata efficacia.

Direct link to Lay Summary Last update: 07.01.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Modulation of Chemokine Responses: Synergy and Cooperativity
Proudfoot Amanda, Uguccioni Mariagrazia (2016), Modulation of Chemokine Responses: Synergy and Cooperativity, in Frontiers in Immunology, 7, 1.
Potential of PEGylated Toll-Like Receptor 7 Ligands for Controlling Inflammation and Functional Changes in Mouse Models of Asthma and Silicosis
Ferreira TP, Mariano LL, Ghilosso-Bortolini R, de Arantes AC, Fernandes AJ, Berni Michele, Cecchinato Valentina, Uguccioni Mariagrazia, Maj R, Barberis A, Silva PM, Martins MA (2016), Potential of PEGylated Toll-Like Receptor 7 Ligands for Controlling Inflammation and Functional Changes in Mouse Models of Asthma and Silicosis, in Frontiers in Immunology, 95.
Chemokine interaction with synergy-inducing molecules: fine tuning modulation of cell trafficking
Cecchinato Valentina, D'Agostino Gianluca, Raeli Lorenzo, Uguccioni Mariagrazia (2015), Chemokine interaction with synergy-inducing molecules: fine tuning modulation of cell trafficking, in J Leukoc Biol, 1.
Innate immune cells express IL-17A/F in acute generalized exanthematous pustulosis and generalized pustular psoriasis
Kakeda M., Schlapbach Christoph, Danelon G., Tang M. M., Cecchinato V., Yawalkar N., Uguccioni M. (2014), Innate immune cells express IL-17A/F in acute generalized exanthematous pustulosis and generalized pustular psoriasis, in Archives of Dermatological Research, 306(10), 933-938.
HMGB1 and leukocyte migration during trauma and sterile inflammation
Venereau Emilie, Schiraldi Milena, Uguccioni Mariagrazia, Bianchi Marco (2013), HMGB1 and leukocyte migration during trauma and sterile inflammation, in Molecular Immunology, 55(1), 76.

Collaboration

Group / person Country
Types of collaboration
Prof. Roberto Speck / University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Marco E. Bianchi / Istituto San Raffaele, Milan Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Amanda Proudfoot / Geneva Research Centre Merck Serono International Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Mario Mellado / Centro Nacional de Biotenología, Madrid Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Costantino Pitzalis / Rheumatology Dept. William Harvey Institute, London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christiane Stahl-Hennig / German Primate Center Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Bernhard Moser/ University of Cardiff Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Enos Bernasconi / Ospedale Civico Lugano Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Giornata della ricerca clinica Talk given at a conference Impairment T-helper cell migration in HIV-1 infection is rescued by modulating actin polymerization 18.03.2016 Lugano, Switzerland Uguccioni Mariagrazia;
Institute for Arthritis Research (iAR) meeting Talk given at a conference HMGB1 controlling CXCL12 activities in Rheumatoid Arthritis 10.12.2015 Lausanne, Switzerland Uguccioni Mariagrazia;
5th ADITEC meeting Talk given at a conference Fine tuning modulation of cell migration to mucosal sites 04.11.2015 Brussels, Belgium Uguccioni Mariagrazia;
4th European Congress of Immunology Talk given at a conference Impairment of CCR6+ and CXCR3+ T helper cell migration in HIV 1 infection is rescued by modulating actin polymerization 07.09.2015 Vienna, Austria Cecchinato Valentina;
12th International Conference on Innate Immunity Crete Talk given at a conference Synergy in the chemokine system: a new model for tuning chemokine activities 22.06.2015 Crete, Greece Uguccioni Mariagrazia;
1st European Chemokine and Cell Migration Conference (ECMC2015) Talk given at a conference Fine tuning modulation of chemokine activities by synergy-inducing molecules 06.06.2015 Villars-sur-Ollon, Switzerland Uguccioni Mariagrazia;
1st European Chemokine and Cell Migration Conference (ECMC2015) Talk given at a conference Impairment of CCR6+ and CXCR3+ T-helper cell migration in HIV-1 infection is rescued by modulating actin polymerization 05.06.2015 Villars-sur-Ollon, Switzerland Cecchinato Valentina;
IX National Conference of the Italian Society of Immunology, Clinical Immunology and Allergology (SIICA) Talk given at a conference CCR6+ T-cell inefficient actin polymerization prevents mucosal reconstitution in long-term antiretroviral therapy treated HIV-positive subjects” and Lorenzo Raeli: “The CXCL12/HMGB1 complex in rheumatoid arthritis 28.05.2014 Florence, Italy Uguccioni Mariagrazia;
European Academy of Dermatology and Venereology (EADV) Talk given at a conference Synergy-inducing molecules controlling cell migration 28.11.2013 Bellinzona, Switzerland Uguccioni Mariagrazia;
Institute for Arthritis Research (iAR) meeting Talk given at a conference The role of chemokine complexes in Rheumatoid arthritis 20.11.2013 Lausanne, Switzerland Uguccioni Mariagrazia;
3rd ADITEC meeting Talk given at a conference Molecules that synergise with chemokines: their activity on leukocyte recruitment 21.10.2013 Brussels, Belgium Uguccioni Mariagrazia;
15th International Congress of Immunology Talk given at a conference Synergy in the chemokine system: a new model for tuning chemokine activities 22.08.2013 Milan, Italy Uguccioni Mariagrazia;
14th Course of Clinical Immunology Talk given at a conference Synergy-inducing chemokines: a new model for chemokine interactions 06.06.2013 Verona, Italy Uguccioni Mariagrazia;
2nd TIMER meeting Talk given at a conference Effects of partial agonists of TLR7 on human leukocytes 28.02.2013 Milan, Italy Cecchinato Valentina;


Awards

Title Year
Premio Circolo della Stampa Pesaro 2016 2016

Associated projects

Number Title Start Funding scheme
137079 Cell migration in tumorigenesis and metastasis 01.01.2012 ProDoc
118048 Impact of multiple chemokine expression in human disease 01.03.2008 Project funding (Div. I-III)
157699 Acquisition of a 600MHz solution NMR spectrometer 01.10.2015 R'EQUIP

Abstract

1.SUMMARY OF THE RESEARCH PLAN1.1 Background: Chemokines are secreted proteins of 67 to 127 amino acids and have emerged as key controllers of integrin function and cell locomotion (1-4). The effects of chemokines are mediated by seven transmembrane domain receptors coupled to GTP-binding proteins which are differentially expressed in a wide range of cell types. The resulting combinatorial diversity in responsiveness to chemokines guarantees the proper tissue distribution of distinct leukocyte subsets under normal and inflammatory/pathological conditions. A vast range of in situ experiments, aimed at understanding which chemokines are produced in specific circumstances, has revealed that a variety of chemokines can be concomitantly produced at target sites of leukocyte trafficking and homing. This renders the chemokine system a good target for therapy, and has increased the search, by pharmaceutical companies, for small molecule chemokine antagonists (5). While we understand well the effects of different chemokines one by one, much less was known about the potential consequences of the expression of multiple chemokines, cytokines (6), toll like receptor ligands (7,8) or different inflammatory molecules (9) on leukocyte migration and function. Our group revealed the existence of additional features of chemokines: they can antagonise or enhance, as synergy-inducing chemokines (10-17), the activity of other chemokines. There is no more doubt that the synergism between chemokines is crucial at the very early stage of inflammation (18), while the study of the role of synergy-inducing chemokines in the tumour microenvironment (17), and of other molecules, such as the alarmin High Mobility Group Box 1 (HMGB1), released in inflammation (19) is at its infancy.1.2 Working Hypothesis: Our group has identified additional mechanisms which can modulate chemokine activities. Beyond their agonistic activity, chemokine can act as synergy-inducing molecules by enhancing the activity of selective chemokine receptors in the presence of the agonist. Moreover, we have identified HMGB1 as the first inflammatory molecule which can enhance the activity of CXCL12, by forming with this chemokine an heterocomplex. Therefore:oThe activity of chemokines on human leukocytes can be modulated by several mechanisms.oThe concomitant expression of natural chemokines that can act in synergism, by forming heterocomplexes, can provoke the enhancement of the effects of individual agonists. oOther molecules, besides HMGB1, which are present in inflammatory conditions, might act similarly to synergy-inducing chemokines by forming heterocomplexes with chemokines, thereby enhancing agonist chemokine activities. 1.3 Specific Aims: We have successfully identified a novel mechanism governing chemokine interactions, characterized several synergy-inducing chemokines, and identified the first chemokine/HMGB1 heterocomplex that enhances CXCL12 activities. We propose to extend our research to: oCharacterize in detail, the activity of chemokines that can provide an additional level of control of leukocyte traffic. Identify the mechanisms that regulate chemokine-chemokine interactions, and receptors responses. oExtend the characterization of synergy-inducing chemokines and of inflammatory molecules acting in synergism with chemokines in inflammatory conditions and tumours. oStudy the details of heterocomplexes between synergy-inducing molecules and chemokine agonists using several approaches (e.g.: Nuclear Magnetic Resonance (NMR), Surface Plasmon Resonance (SPR)). 1.4 Experimental Methods: We have used and will use a variety of in vitro pharmacological and cellular assays on cells transfected with chemokine receptors, as well as on mouse and human leukocytes. We have considerable knowledge of structure, activities, receptor selectivity and expression of several human chemokines. We have extensive experience with all technical aspects, as well as access to all material required. We will select established animal models to validate in vivo the molecules we have identified as candidates for the modulation of leukocyte recruitment via the mechanisms described above. 1.5 Relevance: The identification of chemokines and inflammatory molecules that can synergise with the CCR7, CCR4, CCR2 and CXCR4 agonists has opened a new scene on the chemokine filed. It is without question that chemokines are among the key components controlling leukocyte traffic and function. In such tissue milieu, the activities of individual chemokines can be modified leading to a dramatic change of leukocyte migration and function. However, the consequence of multiple chemokine and/or inflammatory molecule expression in physiology and pathology is still at its infancy. Understanding the mechanisms regulating the activity of chemokines would make possible the production of novel therapies for inflammatory diseases, based on small molecule antagonists with high and specific efficacy targeting not only chemokine agonists, but also the heterocomplexes formed with synergy-inducing molecules.
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