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Studying how chronic inflammation alters epidermal homeostasis using psoriasis as a model disease

English title Studying how chronic inflammation alters epidermal homeostasis using psoriasis as a model disease
Applicant Boehncke Wolf-Henning
Number 175470
Funding scheme Project funding (Div. I-III)
Research institution Hopitaux Universitaires de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.10.2017 - 31.10.2021
Approved amount 572'000.00
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Keywords (6)

homeostasis; psoriasis; Lrig1; cytokines; mechano-transduction; epidermis

Lay Summary (German)

Lead
Wolf-Henning Boehncke
Lay summary

Die Psoriasis ist eine häufige Hautkrankheit. Sie beeinträchtigt nachhaltig die Lebensqualität und Lebenserwartung der Betroffenen. Intensive Interaktionen zwischen Zellen des angeborenen und des erworbenen Immunsystems einerseits sowie zwischen Immunzellen und organständigen Zellen der Haut andererseits stehen im Zentrum der Pathogenese. In diesem Zusammenhang speilt ein bisher wenig beachteter immunologischer Botenstoff, Interleukin 17E (IL-17E), eine wesentliche Rolle. Weiterhin gibt es Hinweise für die Relevanz nicht-immunologischer Faktoren wie z.B. mechanische Einflüsse.

Ziel dieses Projektes ist es, die Rolle von IIL-17E im Rahmen chronischer Entzündungszustände der Haut aufzuklären und die modulierenden Effekte mechanischer Einflüsse dabei zu berücksichtigen. Konkret werden folgende Fragen untersucht:

  • Welche Zellen der Oberhaut produzieren IL-17E, und wie wirkt sich dies auf die Barrierefunktion der Haut aus?
  • Welche Immunzellen in der Haut produzieren IL-17E und wie beeinflussen sie den Entzündungsprozess?
  • Wie unterscheidet sich die IL-17E Produktion bei verschiedenen entzündlichen Hautkrankheiten?
  • Welchen Stellenwert hat IL-17E als Ziel für innovative Therapeutika?
  • Wie modulieren mechanische Faktoren den Entzündungsprozess in der Haut?

Dies ist ein translationelles Projekt: Die Wechselwirkungen zwischen scheinbar unabhängigen pathogenetischen Prozessen sowie die Rolle eines bisher wenig beachteten immunologischen Botenstoffes sollen aufgeklärt werden. Da 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: 09.10.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
IL‐17E, iNOS and Arginase1 as new biomarkers in the identification of neutrophilic dermatoses
Stalder R., Brembilla N., Conrad C., Yawalkar N., Navarini A., Boehncke W.H., Kaya G. (2021), IL‐17E, iNOS and Arginase1 as new biomarkers in the identification of neutrophilic dermatoses, in Clinical and Experimental Dermatology.
IL-25 (IL-17E) in epithelial immunology and pathophysiology
Borowczyk Julia, Shutova Maria, Brembilla Nicolo Costantino, Boehncke Wolf-Henning (2021), IL-25 (IL-17E) in epithelial immunology and pathophysiology, in Journal of Allergy and Clinical Immunology, 148(1), 40-52.
Zytokine der IL‐17‐Familie bei der Psoriasis
Lauffer Felix, Eyerich Kilian, Boehncke Wolf‐Henning, Asadullah Khusru, Beissert Stefan, Ghoreschi Kamran, Schön Michael P. (2020), Zytokine der IL‐17‐Familie bei der Psoriasis, in JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 18(7), 675-681.
IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications
von Stebut Esther, Boehncke Wolf-Henning, Ghoreschi Kamran, Gori Tommaso, Kaya Ziya, Thaci Diamant, Schäffler Andreas (2020), IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications, in Frontiers in Immunology, 10.

Collaboration

Group / person Country
Types of collaboration
Nikhil Yawalkar, Dpt. of Dermatology, Inselspital bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
EULAR (European League Against Rhumatism) Austria (Europe)
- Publication
Olivier Preynat, Laboratory of Therapy and Stem Cells, HUG Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Justyna Drukala, Dpt. of Biology, Cracow Univ. Poland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ali Modarressi, Plastic Surgery Unit, HUG Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Claudia Bürger, Univ.-Hautklinik, Frankfurt Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Gaby Palmer-Lourenco/ Faculty of Medicine, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Curdin Conrad, Univ.-hautklinik Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Arbeitsgemeinschaft Wissenschaftlich-Medizinische Forschung (AWMF)r Germany (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Academy of Dermatology and Venereology (EADV) Talk given at a conference new modes of action to treat psoriasis 29.09.2021 Geneva (virtual), Switzerland Boehncke Wolf-Henning;
Primary Care Academy Talk given at a conference dermatoses fréquentes - le rôle des généralistes 24.09.2021 Montreux, Switzerland Boehncke Wolf-Henning;
European Society of Dermatological Research (ESDR) Talk given at a conference IL-17 isoforms in epidermal homeostasis 22.09.2021 Rotterdam, Netherlands Boehncke Wolf-Henning;
IFPA World Congress Talk given at a conference Can we prevent comorbidity in psoriasis? 02.07.2021 Stockholm, Sweden Boehncke Wolf-Henning;
3rd European Workshop on Skin Immune-Mediated Diseases Talk given at a conference Autoreactive T-cells in inflamatory skin diseases 19.05.2021 Florence, Italy Boehncke Wolf-Henning;
Weiterbildung Rheumaliga Schweiz Talk given at a conference Inhibition von IL-17 und IL-23 - eine neue Strategie zur Behandlung von Psoriasis und Psoriasisarthritis 15.04.2021 Geneva, Switzerland Boehncke Wolf-Henning;
Congress of the Turkish Society for Dermatology Talk given at a conference Why should dermatologists care about psoriatic arthritis? 04.12.2020 Bodrum, Turkey Boehncke Wolf-Henning;
Swiss Psoriasis Day Talk given at a conference Update on GRAPPA activities 31.10.2020 Basel, Switzerland Boehncke Wolf-Henning;
congress of the European Academy for Dermatology and venereology Talk given at a conference therapeutic innovations in psoriasis 11.10.2020 Madrid, Spain Boehncke Wolf-Henning;
Congress of the Serbian Society for Dermatology Talk given at a conference Comorbidities of psoriasis 15.11.2019 Belgrade, Serbien Boehncke Wolf-Henning;
Kogress der Deutschen Dermatologischen Gesellschaft Talk given at a conference therapeutische Innovationen für Psoriasis 02.05.2019 Berlin, Germany Boehncke Wolf-Henning;
Congress of the European Academy for Dermatology and Venereology Talk given at a conference therapeutic innovations for psoriasis 13.07.2018 Paris, France Boehncke Wolf-Henning;
Psoriatic arthritis symposium Talk given at a conference comorbidities in the psoriatic disease 12.07.2018 Toronto, Canada Boehncke Wolf-Henning;


Self-organised

Title Date Place
Grand Colloque 16.09.2021 Geneva, Switzerland
annual congress of the Schweizerische Gesellschaft für dermatologie und venereologie 26.08.2021 Geneva, Switzerland
GRAPA workshop 16.06.2021 Zürich, Switzerland
Grand Colloque 17.10.2019 Geneva, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Psoriatic Arthritis - the most relevant comorbidity of psoriasis Workshop 03.06.2021 Zug, Switzerland Boehncke Wolf-Henning;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Swiss Psoriasis Day léman bleu Western Switzerland 2020

Awards

Title Year
Poster Prize/European Society for Dermatological Research (ESDR) 2021
Lilly Immunodermatology Award 2020

Patents

Title Date Number Inventor Owner
cellular substitutes and methods of preparation thereof 30.09.2019 19198711.4

Associated projects

Number Title Start Funding scheme
152680 The interplay between IL-17 isoforms, store-operated calcium influx, and insulin resistance in psoriasis 01.10.2014 Project funding (Div. I-III)
152680 The interplay between IL-17 isoforms, store-operated calcium influx, and insulin resistance in psoriasis 01.10.2014 Project funding (Div. I-III)

Abstract

Psoriasis is a common skin disease, characterized by severe chronic inflammation in the dermis and perturbed homeostasis of the epidermal epithelium. These observations are indicative of an extensive cross-talk that takes place between resident cells of the skin and the inflammatory environment, the details of which are only beginning to be understood. Recent investigations have highlighted the important role of the Th17/IL-23 pathway in psoriasis, and have identified the IL-17A isoform as a critical mediator of the disease. Our laboratory has recently demonstrated that IL-17E, an other IL-17 isoform, is highly up-regulated in psoriatic skin, and has evidence that it participates in the communication between the epidermis and immune cells located in the neighbouring dermis. IL-17E may therefore represent an important molecular mediator of epidermal-immune cross-talk and thus have important functions during epidermal homeostasis in inflammatory skin diseases. This research proposal therefore aims to determine the functional role of IL-17E in the skin and to elucidate the cellular and molecular mechanisms by which it exerts its affects. In addition, we will establish the relevance of two exciting themes that are emerging in the field of inflammation biology. These are; 1) the role of Lrig1 in regulating cutaneous inflammatory responses and epidermal homeostasis, and 2) the link between chronic inflammation and altered tissue mechanical cues in disease. Evidence from several studies indicates that both Lrig1 and mechanotransduction are critical in cutaneous homeostasis and are aberrantly regulated in cutaneous inflammatory disease. Our purpose is therefore to determine their functional importance during pathogenesis and to explore their role in the context of other pro-inflammatory mediators such as IL-17E.The proposed research programme will adopt a modular framework, as summarised below. MODULE1 - DEFINING THE ROLE OF IL-17E IN PSORIASIS•Aim 1: Expression of IL-17E in the epidermis and its role in barrier homeostasis.•Aim 2: IL-17E in the dermis, role of macrophages in psoriatic inflammation.•Aim 3: IL-17E in distinct inflammatory conditions and impact of targeted therapeutic intervention.•Aim 4: Determining the functional relevance of IL-17E in mouse models of cutaneous inflammation. MODULE 2 - EXPLORATORY AVENUES•Aim 1: Defining the role of Lrig1 regulated receptor tyrosine kinases in psoriasis•Aim 2: The role of tissue mechanical cues in promoting abnormal epidermal homeostasisTo address the aims outlined above, we will employ a variety of in vitro and in vivo approaches using human clinical samples and animal models of disease respectively. We will also utilise a powerful collaborative network we have established both within our host institute and with external research groups. Collectively, the research programme we are proposing will significantly advance our understanding of the pathogenic mechanisms that operate in psoriasis and will enable the development of novel therapeutic strategies for the treatment of the disease.
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