Molecular and cellular events driving the pathogenic innate type 2 response in barrier-defective atopic skin Exaggerated type 2 immunity is central in the pathogenesis of atopic diseases, including atopic 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 understood. In atopic dermatitis, uncontrolled innate type 2 immunity in the skin plays a central role for development of skin inflammation but also for the associated systemic TH2 bias responsible for allergy and asthma that manifest in a large fraction of cases. Intriguingly, genetic studies have revealed that a major genetic association of atopic dermatitis is with defects of genes involved in epidermal barrier formation and maintenance. Loss-of-function mutations in the gene encoding filaggrin, a protein required for coordinated cornification 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 deregulated 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 will use a particularly relevant mouse model, filaggrin knock out mice on the BALB/c background, which reproduce the key features of the 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 macrophages and innate lymphoid cells contribute to the disease. We will finally clarify whether E-cadherin-mediated counter-regulation regulates the inflammation of barrier-defective skin. Our experiments will yield important new insight into the pathogenesis of atopic dermatitis, hopefully instructing the design of new therapeutic approaches.
|Effective start/end date||1/01/17 → …|
- Deutsche Forschungsgemeinschaft