FOR2599Project 8

Molecular and cellular events driving the pathogenic innate type 2 response in barrier-defec- tive atopic skin

Axel Roers, Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden

Rolf Jessberger, Institute for Physiological Chemistry, Medical Faculty Carl Gustav Carus, TU Dresden

Filaggrin is a protein found only in the upper layers (green uorescence, le panel) of the skin and is essential for coordinated formation of the corni ed layer, our outermost shield against the environment. Genetic defects of Filaggrin result in impaired skin barrier function with very dry and scaly skin. Complete absence of functional laggrin is the cause of the heritable skin disease Ichtyhyosis vulgaris (right panel). Intriguingly, these patients frequently su er from severe ‘atopy‘, i.e. they develop massive allergy, eczema and asthma. This means that a skin barrier defect primarily a ecting only the skin, drives the entire immune system toward ‘all- ergic’ (‘type 2’) responses. Our project aims to elucidate which molecules and cells contribute to this allergic deviation of the immune system ensuing from skin barrier defects.

Summary

Exaggerated type 2 immunity is central in the pathogenesis of atopic diseases, including ato- pic dermatitis, which represents a major socioeconomic problem in western countries. Type 2 immunity is key for the control of helminthic parasites, tissue repair and homeostasis of some tissues but can also be detrimental if activated in an uncontrolled manner. While the adaptive arm of type 2 immunity, i.e. TH2 and IgE functions, have been extensively studied, mechanisms of induction and regulation of innate type 2 responses of tissues are far less un- derstood. In atopic dermatitis, uncontrolled innate type 2 immunity in the skin plays a central role for development of skin in ammation

but also for the associated systemic TH2 bias responsible for allergy and asthma that mani- fest in a large fraction of cases. Intriguingly, genetic studies have revealed that a major ge- netic association of atopic dermatitis is with defects of genes involved in epidermal barrier formation and maintenance. Loss-of-function mutations in the gene encoding laggrin, a protein required for coordinated corni cation of keratinocytes, are strongly associated with atopic dermatitis and asthma, indicating that defects of an epidermal structural protein can contribute to induction of exaggerated local type 2 immunity in the skin and lead to deregula- ted systemic TH2 responses. The task of this project is to elucidate mechanisms that trigger, perpetuate, and counter-regulate pathogenic type 2 immune responses in barrier-defective skin. We use a particularly relevant mouse model, laggrin knock out mice, which reproduce the key features of human atopic disease. We aim to identify the pattern recognition receptors of the innate immune system and the cytokines responsible for exaggerated type 2 responses of barrier-defective skin. We will also determine whether eosinophils, mast cells, M2 macro- phages and innate lymphoid cells contribute to the disease. We will nally clarify whether E-cadherin-mediated counter-regulation regulates the in ammation of barrierdefective skin. Our experiments will hopefully instruct the design of new therapeutic approaches to atopic diseases.

Selected publications

Roers group

Ghouse SM, Polikarpova A, Muhandes L, Dudeck J, Tantcheva-Poór I, Hartmann K, Lesche M, Dahl A, Eming S, Müller W, Behrendt R, Roers A. Although Abundant in Tumor Tissue, Mast Cells Have No Effect on Immunological Micro-milieu or Growth of HPV-Induced or Transplanted Tumors. Cell Rep. 2018;22:27-35

Chmelar J, Chatzigeorgiou A, Chung KJ, Prucnal M, Voehringer D, Roers A, Chavakis T. No Role for Mast Cells in Obesity-Related Metabolic Dysregulation. Front Immunol. 2016;7:524.

Peschke K, Weitzmann A, Heger K, Behrendt R, Schubert N, Scholten J, Voehringer D, Hartmann K, Dudeck A, Schmidt-Supprian M, Roers A. I?B kinase 2 is essential for IgE-induced mast cell de novo cytokine production but not for degranulation. Cell Rep. 2014;8:1300-7.

Dudeck A, Dudeck J, Scholten J, Petzold A, Surianarayanan S, Köhler A, Peschke K, Vöhringer D, Waskow C, Krieg T, Müller W, Waisman A, Hartmann K, Gunzer M, Roers A. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 2011;34:973-84.

Scholten J, Hartmann K, Gerbaulet A, Krieg T, Müller W, Testa G, Roers A. Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res. 2008;17:307-15.

Jessberger group

Under construction