Proteomic and pharmacological approaches to decipher molecular mechanisms regulating endogenous IL-33 protein expression and release – PROTEOMICS-IL33

Allergic diseases such as asthma, allergic rhinitis and eczema are common diseases that affect many patients from childhood to adulthood. According to World Health Organization estimates, there are currently 235 million people worldwide who suffer from asthma. It is therefore very important to provide a better understanding of the fundamental mechanisms of allergic reactions.
Large-scale genetic studies involving thousands of patients have repeatedly identified two major genes predisposing to asthma, the genes encoding Interleukin-33 (IL-33) and its receptor (ST2). IL-33 is a protein that belongs to the family of interleukins, soluble messengers that allow cells to communicate with each other and that play a major role in tissue inflammation. This protein, stored in blood vessels and epithelial barriers (lungs, skin, ...) is released upon tissue damage. It acts as an alarm signal, which warns the organism during a trauma or an infection by stimulating many cells of the immune system, in particular different types of white blood cells involved in allergic reactions (lymphocytes, eosinophils, mast cells, group 2 innate lymphoid cells).
People with a lower amount of IL-33 protein in the body due to a genetic mutation in the IL33 gene are less likely to develop allergic asthma or rhinitis. The IL-33 protein is thus a promising therapeutic target for asthma and other allergic diseases, and clinical trials with blocking antibodies are currently underway (Phase II). However, many unknowns remain regarding the biology and biochemistry of the protein. Among the important questions that remain to be answered:
- How are the amounts of IL-33 protein in producer cells determined?
- How are the IL-33 proteins released in the extracellular medium upon exposure to environmental allergens or mechanical stress ?
The main objective of our project is to provide answers to these two fundamental questions. To achieve this objective, we will combine approaches of protein biochemistry, proteomics (identification of thousands of proteins by high-throughput mass spectrometry), molecular and cellular biology, functional genomics and pharmacology (use of small molecules inhibitors).
In view of our expertise, available tools / methods, and results already obtained, we predict that the project will lead to several major advances in the understanding of the biology of IL-33 and the mechanisms involved in allergic inflammatory reactions. The project could also open up promising therapeutic prospects that are less costly than the use of monoclonal antibodies for the treatment of asthma and other allergic diseases.
A key asset of the project is the complementarity and multidisciplinarity of the two participating teams, and the long-term expertise on IL-33 (> 15 years) of the coordinating team, one of the leading teams on the topic at the international level.