The IL-18 Conundrum: Investigating the role of IL-18 the pathogenesis of atopic dermatitis

Grantee: Christoph Schlapbach, Associate Professor, Inselspital, Bern University Hospital, University of Bern

Amount: DKK 3,942,000

Grant category: Research Grants in open competition

Year: 2024

Geography: Switzerland

Christoph Schlapbach’s project aims to elucidate the role of interleukin (IL-)18 in atopic dermatitis (AD), a prevalent, chronic skin disease with significant burden and unmet therapeutic needs.

IL-18 is linked to AD pathogenesis by multiple lines of evidence: IL-18 receptor (IL-18R) gene variants associate with AD susceptibility, IL-18 levels correlate with disease severity, and animal models of AD suggest a pro-inflammatory function of IL-18 in type 2 skin inflammation. Yet, the functional link between IL-18, considered a Th1-promoting cytokine, and AD, a Th2-driven disease, remains obscure. Christoph Schlapbach’s preliminary data now indicate that (i) there is a functional link between AD-associated IL18R gene variants and heightened Th2-cell responses, (ii) IL-18 can promote secretion of pathogenic cytokines in Th2 cells of AD patients, and (iii) skin explants from lesional AD skin can be used to model the effects of IL-18 in the complex environment of human skin.

Christoph Sclapbach’s project will leverage genotype-phenotype-function studies in a translational approach to dissect the mechanisms by which IL-18 influences Th2 cell-mediated inflammation in AD. Utilizing state-of-the-art methodology and functional validation experiments, the study aims to clarify IL-18’s role in AD pathogenesis to answer this long-standing conundrum in the fields of dermatology and immunology.

The results of Christoph Schlapbach’s project may provide a new understanding of IL-18’s role in AD, potentially enabling improved treatment.

Repair Glia: An Overlooked Cell Type Orchestrating Skin Wound Healing

Grantee: Lukas Sommer, Professor, University of Zurich

Amount: DKK 3,781,580

Grant category: Research Grants in open competition

Year: 2024

Geography: Switzerland

Lukas Sommer’s project explores the mechanisms mediating the role of repair glia in skin wound healing by means of genetically engineered mouse models and an organotypic 3D culture system of human skin wounds.

Inefficient skin wound healing can cause severe medical problems, including chronic wounds and ulcers. Innervation is a critical player in tissue regeneration and repair. While most studies have linked this effect to signaling from axons, there is increasing evidence for peripheral glia contributing to successful wound healing. Lukas Sommer’s laboratory has recently shown that peripheral glia following skin injury to become repair glia, which promote the wound healing process by paracrine signaling. In his project, single cell RNA sequencing on the cellular microenvironment in presence or absence of repair glia at defined timepoints after skin injury will be performed and complemented with spatial omics approaches to characterize the gene expression profile of repair glia and to identify their mode of intercellular communications with other skin cell types. Multiplex optical imaging approaches on biopsies of murine and human skin lesions will allow the investigation of the relevance of our findings in human skin diseases. Finally, functional validation of key candidate factors in mice and in 3D reconstituted human skin wounds will determine how repair glia promote the wound healing process and which signaling pathways could potentially represent targets for treatment.

Lukas Sommer’s project therefore aims to enhance our understanding of wound healing mechanisms with potential broad applications in medicine.

Single-cell ribosome profiling to monitor the translational landscape in skin wound healing

Grantee: Ataman Sendoel, Assistant Professor, University of Zurich

Amount: DKK 3,979,800

Grant category: Research Grants in open competition

Year: 2024

Geography: Switzerland

Ataman Sendoel’s project seeks to improve our understanding of how genes are translated to protein during wound healing and clarify the potential of the involved pathways as drug targets.

Impaired wound healing poses a substantial medical challenge, particularly among the elderly. Understanding the gene expression changes during wound repair is therefore essential for devising new strategies to enhance wound healing in aging and disease.

While transcriptional (i.e., going from DNA to messenger-RNA) control has been extensively studied in the skin, recent studies have indicated that cellular behavior is strongly coupled to the regulation of translation (i.e., going from messenger-RNA to protein). However, how translation is controlled during wound repair and how its deregulation mechanistically contributes to impaired wound repair in aging remains unknown.

In this project, Ataman Sendoel and his team will exploit an in vivo strategy to comprehensively map the function of the translational landscape in skin wound healing. Leveraging a single-cell ribosome (an intracellular protein complex that translates messenger-RNA to protein) profiling strategy in vivo, the team will monitor skin cells during different wound healing stages. By coupling this with single-cell RNA sequencing, they will determine cell-type-specific translational efficiencies and identify factors relevant to wound repair in aging.

Finally, Ataman Sendoel and his team aim to carry out a mini-screen to identify FDA-approved drugs that selectively increase the translational efficiency of skin wound repair factors.

Collectively, these data will provide systematic insights into the translational landscape of skin wound repair, and how deregulated translation leads to impaired wound repair. It may also clarify if protein synthesis pathways could be targeted therapeutically to restore wound healing.

The NLRP1 inflammasome in keratinocytes: A novel target for the treatment of inflammatory skin diseases

Grantee: Hans-Dietmar Beer, Principal Investigator, University Hospital Zürich

Amount: DKK 2,072,266

Grant category: Research Grants in open competition

Year: 2023

Geography: Switzerland

This project by Hans-Dietmar Beer aims to elucidate the molecular mechanisms associated with NLRP1 inflammasome activation in keratinocytes in inflammatory skin conditions.

Inflammasomes are protein complexes, which are mainly expressed by immune cells. Upon detection of stress factors, they regulate activation of the proinflammatory cytokine proIL-1β and its release to the extracellular environment, thereby inducing inflammation. Inflammasomes are required for initiation of normal immune responses, however, their chronic activation also underlies the pathogenesis of numerous inflammatory diseases.

The epidermis, the outermost layer of our skin, represents the first line of defense of the human body and consists of densely packed layers of keratinocytes. These cells express high levels of all proteins of the NLRP1 inflammasome. To address the roles of this inflammasome in human skin, Hans-Dietmar Beer and his team previously activated NLRP1 in keratinocytes cultivated together with dermal fibroblasts (connective tissue cells) in a three-dimensional (3D) organotypic skin model and found that NLRP1 activation induced an altered tissue phenotype and activation of pathways associated with inflammatory skin diseases. Most importantly, the team also detected inflammasome activation in keratinocytes in biopsies of patients suffering from these conditions.

The preliminary results suggest that inhibition of NLRP1 activation in keratinocytes might represent a novel therapeutic strategy for patients with certain inflammatory skin diseases and the current proposal seeks to investigate this hypothesis in more detail.

The aryl hydrocarbon receptor integrates signals from the commensal yeast Malassezia to attenuate inflammation in the atopic skin

Grantee: Salomé LeibundGut-Landmann, Professor, University of Zurich

Amount: DKK 4,199,654

Grant category: Research Grants in open competition

Year: 2022

Geography: Switzerland

With this project, Salomé LeibundGut-Landmann along with collaborator Giuseppe Ianiri aims to investigate the importance of aryl hydrocarbon receptor (AhR) activation in relation to treatment of allergic skin reactions, including atopic dermatitis.

AhR is a so-called transcription factor, activated by cyclic (aromatic) compounds, which regulates cellular signaling. It is known that AhR is important for maintaining the skin barrier and a healthy cutaneous immune system and Salomé and her team propose that this, at least in part, is regulated by the release of such aromatic compounds by the commensal (non-pathogenic) and very common skin fungal class, Malassezia.

Using both human keratinocytes and mouse models, this hypothesis will be tested and the biosynthetic pathways of aromatic binding partners (ligands) for Ahr produced by Malassezia strains will be characterized.

If successful, the understanding of the interplay between commensal fungi as part of the skin microbiome and cellular maintenance of the skin barrier could provide novel approaches for treating allergic reactions and other skin inflammatory conditions, like atopic dermatitis.

Investigating the regulation of Interleukin-36 cytokine activity in the pathogenesis of generalised pustular psoriasis

Grantee: Mark Mellett, Group Leader, University Hospital Zürich

Amount: DKK 2,055,914

Grant category: Research Grants in open competition

Year: 2022

Geography: Switzerland

The overall aim of Mark Mellett’s project is to shed light on the differences and the mechanisms governing regulation of IL-36 activity in both skin inflammation and viral infection.

IL-36 cytokines (a substance secreted by cells that affect the response of nearby cells) are well-known to contribute to inflammatory skin diseases in particular generalised pustular psoriasis. Yet the mechanisms regulating the activitiy of the cytokines remain poorly understood.

Mark and his team suggest that IL-36 is an important response mechanism protecting the skin against viral infection and this response is “switched on” in error in generalised pustular psoriasis. They propose to elucidate the reasons for this to better understand how pustular psoriasis is triggered.

Atopic dermatitis in Sub-Saharan Africa: exploring immune phenotypes and mycobiome

Grantee: Marie-Charlotte Brüggen, Assistant Professor, University Hospital Zürich

Amount: DKK 1,886,076

Grant category: Research Grants in open competition

Year: 2020

Geography: Switzerland

The goal of this project is to improve the understanding of atopic dermatitis (AD) in Sub-Saharan Africa by characterizing the immune responses and potential changes in the associated skin and gut mycobiome (the composition of fungi found in a defined area) in AD patients from a dermatological clinic in Moshi, Tanzania. Subsequently, the results will be compared with equivalent data from Central European AD patients to identify similarities and differences.

As previous studies in this area is practically non-existing, this study will be a first step towards understanding the immune phenotype of Sub-Saharan Africa AD and how environmental factors like the fungi of the skin and gut could influence it. This will be important with regard to future treatment options of AD in the region.

Thermal Imaging in dermatology – Creation of the first database for artificial intelligence-based diagnostics

Grantee: Professor Alexander Navarini, Department of Dermatology and Allergy, University Hospital Basel

Amount: DKK 1,180,760

Grant category: Research Grants in open competition

Year: 2019

Geography: Switzerland

Thermal imaging is an investigational tool whose advantages are undisputed in engineering, i.e. for the non-destructive testing of composite materials, or in the photovoltaic industry.

The technique consists in measuring and imaging the thermal radiation and to convert this information into temperature maps, or thermograms. Medical applications of thermal imaging exhibit great potential and the field is currently experiencing a renaissance. One reason is probably the recent dramatic improvements of infrared cameras that are now affordable and compact and can even be connected to smartphones.

This project aims to produce a full body thermal imaging scanner for patients to later use as a next generation diagnostic tool, coupled with a 360° 2- and 3-dimensional digital photography device.

Our goal is to create the first open access skin thermograms database, large enough to enable artificial intelligence analysis. Such a tool could be very useful for the quantification and potentially prediction of affected areas in different skin disease such as psoriasis and eczema.