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The interplay between IL-17 isoforms, store-operated calcium influx, and insulin resistance in psoriasis

English title The interplay between IL-17 isoforms, store-operated calcium influx, and insulin resistance in psoriasis
Applicant Boehncke Wolf-Henning
Number 152680
Funding scheme Project funding (Div. I-III)
Research institution Département de Neurosciences Cliniques Hôpitaux Universitaires de Genève Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.10.2014 - 30.09.2017
Approved amount 376'776.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (5)

store-operated calcium influx; TH17 lymphocytes; keratinocytes; insulin resistance; psoriasis

Lay Summary (German)

Lead
Psoriasis ist eine häufige, chronisch-entzündliche Hautkrankheit. Sie beeinträchtigt nachhaltig die Lebensqualität der Betroffenen sowie deren Lebenserwartung. Letzteres wird durch weitere Krankheiten verursacht (z.B. das metabolische Syndrom), die häufig mit Psoriasis assoziiert sind. Die Integration wesentlicher Befunde aus unterschiedlichen Bereichen der biomedizinischen Forschung hat das Verständnis für die Pathogenese der Psoriasis sowie deren Assoziation mit weiteren Erkrankungen verbessert. Dieser Fortschritt leitet eine qualitative Verbesserung der Patientenversorgung weg von primär Symptom-orientierten Therapien hin zu einem umfassenden Langzeit-Management dieser bisher unheilbaren Krankheit ein.
Lay summary

Inzwischen ist bekannt, dass intensive Interaktionen zwischen Zellen des angeborenen und des erworbenen Immunsystems stattfinden. Daraus resultiert eine funktionelle Veränderung auch organständiger Zellen (z.B. in der Haut), die sich ihrerseits auf das Immunsystem auswirkt. Ziel dieses Projektes ist zu verstehen, wie chronische Entzündung in organständigen Zellen einen Zustand der Resistenz gegenüber Insulin induziert, einem Botenstoff, der bisher in erster Linie im Zusammenhang mit metabolischen Erkrankungen wie Diabetes mellitus untersucht wurde. Diese Insulinresistenz erklärt nicht nur viele der Psoriasis-typischen Hautveränderungen, sondern sie wirkt sich auch auf die Funktion des Immun- und des kardiovaskulären Systems aus. Zusätzlich beeinflussen weitere Mediatoren wie z.B. Kalzium die Zellfunktion. Dieses Projekt beleuchtet speziell die Interaktion zwischen Immun- und Hautzellen und fokussiert dabei auf Faktoren (die Familie der Interleukin 17 Mediatoren und den Kalziumkanal Orai1), für die bereits erste Hinweise auf eine Relevanz bei einem klinisch gut definierten Krankheitsbild vorliegen, nämlich der Psoriasis.    

Dies ist ein translationelles Projekt: Die Wechselwirkungen zwischen scheinbar unabhängigen pathogenetischen Prozessen sollen aufgeklärt werden. Da dies am Beispiel einer häufigen Krankheit erfolgt und die meisten beteiligten Faktoren potenzielle Ziele für innovative Therapien darstellen, sind die Ergebnisse von direkter klinischer Bedeutung, speziell für die Behandlung der Psoriasis, potenziell aber auch für Patienten mit anderen chronisch-entzündlichen Krankheiten. 

 

Direct link to Lay Summary Last update: 31.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond
Brembilla Nicolo Costantino, Senra Luisa, Boehncke Wolf-Henning (2018), The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond, in Frontiers in Immunology, 9, 1682-1688.
The role of IL-23 and the IL-23/T H 17 immune axis in the pathogenesis and treatment of psoriasis
Girolomoni G., Strohal R., Puig L., Bachelez H., Barker J., Boehncke W.H., Prinz J.C. (2017), The role of IL-23 and the IL-23/T H 17 immune axis in the pathogenesis and treatment of psoriasis, in Journal of the European Academy of Dermatology and Venereology, 1.
IL-17A localizes in the exocytic compartment of mast cells in psoriatic skin
Brembilla N.C., Stalder R., Senra L., Boehncke W.-H. (2017), IL-17A localizes in the exocytic compartment of mast cells in psoriatic skin, in British Journal of Dermatology, 1.
Unmet Needs in the Field of Psoriasis: Pathogenesis and Treatment
Boehncke Wolf-Henning, Brembilla Nicolo Costantino (2017), Unmet Needs in the Field of Psoriasis: Pathogenesis and Treatment, in Clinical Reviews in Allergy & Immunology, 1.
Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation
Buerger Claudia, Shirsath Nitesh, Lang Victoria, Berard Alina, Diehl Sandra, Kaufmann Roland, Boehncke Wolf-Henning, Wolf Peter (2017), Inflammation dependent mTORC1 signaling interferes with the switch from keratinocyte proliferation to differentiation, in PLOS ONE, 12(7), e0180853-e0180853.
Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition
Fernandez Marylise, Sutterlüty-Fall Hedwig, Schwärzler Christoph, Lemeille Sylvain, Boehncke Wolf-Henning, Merat Rastine (2017), Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition, in Cancer Medicine, 6(7), 1652-1664.
Dermal adipocytes’ claim for fame in psoriasis
Brembilla Nicolò Costantino, Boehncke Wolf-Henning (2017), Dermal adipocytes’ claim for fame in psoriasis, in Experimental Dermatology, 26(5), 392-393.
Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis
Senra Luisa, Stalder Romaine, Alvarez Martinez David, Chizzolini Carlo, Boehncke Wolf-Henning, Brembilla Nicolò Costantino (2016), Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis, in Journal of Investigative Dermatology, 136(10), 1970-1980.
Psoriasis and Psoriatic Arthritis: Flip Sides of the Coin?
Boehncke W (2016), Psoriasis and Psoriatic Arthritis: Flip Sides of the Coin?, in Acta Dermato Venereologica, 96(4), 436-441.
Psoriasis
Boehncke Wolf-Henning, Schön Michael P (2015), Psoriasis, in The Lancet, 386(9997), 983-994.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Carlo Chizzolini, Dpt. of Allergology and Immunology, Geneva University Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Gürkan Kaya, Department of Dermatology, Geneva University Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Claudia Bürger, Dpt. of Dermatology, Goethe University Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Laurent Bernheim, Department of Neurosciences, Geneva University Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Dr. Michel Gillet, Dpt. of Dermatology, Lausanne University Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
3rd PhD retreat, Faculty of Medicine of the University of Geneva Talk given at a conference IL-17E favors neutrophil recruitment in psoriasis by activating M2 macrophages to produce IL-8 in a p38 dependnet manner 27.04.2017 Champery, France Da Fonte Senra Luisa Margarida;
Arbeitsgemeinschaft Dermatologische Forschung (ADF) meeting 2017 Talk given at a conference IL-17E favors neutrophil recruitment in psoriasis by activating M2 macrophages to produce IL-8 in a p38 dependent manner 09.03.2017 Gottingen, Germany Da Fonte Senra Luisa Margarida; Boehncke Wolf-Henning;
29th Meeting of the Swiss Immunology PhD students Talk given at a conference IL-17E favor the recruitment of neutrophils in psoriasis via macrophage activation 06.02.2017 Ermatingen, Switzerland Da Fonte Senra Luisa Margarida;
46th annual European Society for Dermatological Research (ESDR) meeting 2016 Talk given at a conference IL-17E favors the recruitment of neutrophils in psoriasis via macrophage activation 07.09.2016 Munich, Germany Da Fonte Senra Luisa Margarida; Boehncke Wolf-Henning;
4th European Congress of Immunology (ECI) Talk given at a conference Lesional skin of psoriatic patients is characterized by an overexpression of IL-17E producing keratinocytes and IL-17E positive dermal macrophages 06.09.2016 Vienna, Austria Da Fonte Senra Luisa Margarida; Boehncke Wolf-Henning;
Jahrestagung der Schweizerischen gesellschaft für Dermatologie udn Venereologie Talk given at a conference Role of interleukin 17 in the pathogenesis of psoriasis 25.08.2016 Genf, Switzerland Boehncke Wolf-Henning;
Arbeitsgemeinschaft Dermatologische Forschung (ADF) meeting 2016 Poster In-depth characterization of the expression of IL-17 isoforms in psoriasis 10.03.2016 Vienna, Austria Boehncke Wolf-Henning; Da Fonte Senra Luisa Margarida;
2nd PhD retreat, Faculty of Medicine of the University of Geneva Poster IL-17E induces an inflammatory response in monocyte-derived macrophages 01.10.2015 Leysin, Switzerland Da Fonte Senra Luisa Margarida;
Arbeitsgemeinschaft Dermatologische Forschung (ADF) meeting 2015 Poster Over-representation of IL-17E producing keratinocytes and IL-17E positive macrophages in the lesional skin of psoriatic patients 07.03.2015 Ulm, Germany Da Fonte Senra Luisa Margarida; Boehncke Wolf-Henning;


Self-organised

Title Date Place
GRAPPA workshop on psoriatic disease 24.11.2016 Stockholm, Sweden
GRAPPA workshop on psoriatic disease 13.10.2016 London, Great Britain and Northern Ireland
Jahrestagung der Schweizerischen Dermatologischen Gesellschaft 25.08.2016 Genf, Switzerland
GRAPPA workshop on psoriatic disease 12.02.2016 Leeds, Great Britain and Northern Ireland
GRAPPA workshop on psoriatic disease 28.01.2016 Mailand, Italy

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Site Event on the occasion of the WHO General Assembly Talk 24.05.2017 Genf, Switzerland Boehncke Wolf-Henning;


Awards

Title Year
Lilly Immunodermatology Award 2017
Lilly Scholarship (travel grant to attend the Annual ESDR Conference 2017 in Salzburg, Austria) 2017
Travel Grant from the International Cytokine & Interferon Society (ICIS) (travel grant to attend the Cytokine meeting 2017 in Kanazawa, Japan) 2017
Travel Grant from the European Society of Dermatological Research (ESDR) (travel grant to attend the annual ESDR conference 2016 in Munich, Germany) 2016

Associated projects

Number Title Start Funding scheme
175470 Studying how chronic inflammation alters epidermal homeostasis using psoriasis as a model disease 01.10.2017 Project funding (Div. I-III)
175470 Studying how chronic inflammation alters epidermal homeostasis using psoriasis as a model disease 01.10.2017 Project funding (Div. I-III)

Abstract

Psoriasis is a common skin disease, characterized by cutaneous inflammation and hyperproliferation as well as altered differentiation of keratinocytes. Understanding psoriasis pathogenesis advances through integration of key findings in different fields of research. It is now clear that an intense cross-talk takes place between cells of the adaptive as well as the innate immune system, affecting also the functional state of resident cells of the skin, namely endothelial cells and keratinocytes, which in turn feed back to immune cells. Furthermore, there is consensus regarding the central role of TH17 cells. Inflammation-induced insulin resistance attracts more and more attention as a mechanism explaining both endothelial dysfunction (and thus cardiovascular comorbidities) as well as “epithelial dysfunction” (and thus much of psoriasis’ epidermal phenotype). Finally, store-operated calcium entry is now known to be important for both T-cell and keratinocyte function. The proposed project intends to help integrating these novel findings by analysing in detail the interplay of TH17 cells and keratinocytes through all IL-17 isoforms with emphasis on Orai1-mediated store-operated calcium entry and insulin resistance. The specific aims are as follows:•Ex vivo mapping of cells producing IL-17 isoforms, expressing IL-17 receptors, and Orai1 expression in healthy and diseased human skin •In vitro analyses of effects mediated by IL-17 isoforms on the functional state of keratinocytes•In vitro characterization of the main signaling pathways and molecules involved in IL-17 mediated effects in T-cells and keratinocytes •In vitro analysis of Orai1 expression and function in skin- and blood-derived TH17•In vitro analyses on the impact of Orai1-mediated calcium influx on insulin receptor signalling in keratinocytes•In vivo analyses on therapeutic effects of inhibiting store-operated calcium influx in mouse models of cutaneous inflammation/psoriasis The results are of direct clinical importance, as TH17 cells, IL-17, Orai1 and kinases involved in insulin receptor signaling are all valid targets for innovative therapeutic strategies in inflammatory disorders in general and psoriasis in particular.
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