The IL-33/ILC2 axis in allergic inflammation – IL33-ILC2-ALLERGY

Allergic inflammation and type 2 immune responses mediated by T helper 2 (Th2) cells, eosinophils, mast cells, basophils and dendritic cells, and type 2 cytokines (IL-4, IL-5, IL-9, IL-13), play important roles in allergic diseases such as asthma, atopic dermatitis, allergic rhinitis, and allergic conjunctivitis. These inflammatory diseases are common diseases affecting patients from childhood to old age. Indeed, up to 300 million people are suffering from asthma worldwide. Despite advances in treatment, there remains significant unmet therapeutic need. Identification and validation of novel targets is thus critical in order to develop future treatments for those who do not respond to available therapies. The major objective of our project ‘IL33-ILC2-ALLERGY’ (a basic research project) is to provide a better understanding of the interleukin-33 (IL-33)/ ILC2 (group 2 innate lymphoid cells) axis, that is critically involved in allergic inflammation and asthma.

IL-33 is a nuclear cytokine from the IL-1 family abundantly expressed in barrier tissues (lungs, stomach, skin) that was initially discovered by the coordinator of the present project as a nuclear factor of high endothelial venules (NF-HEV) in lymphoid organs. IL-33 functions as an alarm signal (alarmin) released upon tissue damage to alert various types of immune cells expressing the IL-33 receptor ST2, including Th2 cells, mast cells, and group 2 innate lymphoid cells (ILC2s, a novel lineage negative innate lymphoid cell type). Studies performed over the past five years indicate that ILC2s, which produce extremely high amounts of the Th2 cytokines IL-5 and IL-13 in response to IL-33, and play critical roles in type-2 immunity, allergic inflammation and eosinophil homeostasis, are major targets of IL-33 in vivo. Analysis of patient samples and studies in murine models support a crucial role of the IL-33/ILC2 axis in allergic inflammation in different tissues (lung, nasopharynx, skin) and diseases (asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis). Interestingly, genetic studies suggest a major role for this axis in human asthma. Indeed, IL-33 and ST2 were reproducibly identified in all major genome-wide association studies of asthma, and several other genes important for ILC2 biology were also identified as susceptibility loci in some of these studies.

Although the IL-33/ILC2 axis constitutes a promising target for asthma and other allergic diseases, many questions remain to be answered. The objective of our project ‘IL33-ILC2-ALLERGY’ is to address several unresolved and important issues in IL-33 and ILC2 biology:
1) the molecular mechanisms involved in the rapid activation of the IL-33/ILC2 axis following allergen challenge (AIM 1);
2) the cooperation between IL-33 and other signals in the activation of ILC2s (AIM 2);
3) the mechanisms regulating the recruitment of ILC2s into inflamed tissues during allergic inflammation (AIM 3).
The project will significantly increase the current knowledge about two critical molecular (IL-33) and cellular (ILC2s) actors involved in inflammatory allergic reactions, and it will thus contribute to develop fundamental knowledge that could help prevent and treat allergic diseases.

The project is a multidisciplinary collaborative project at the frontier of many disciplines (immunology, allergy, inflammation, vascular biology, molecular and cellular biology, proteomics and bioinformatics, …). The complementary expertise of the participants in molecular and cellular immunology, intravital microscopy (Team 1), proteomics and bioinformatics (Team 2) will be a key asset. The project will also greatly benefit from the facilities and tools available at IPBS (including several knock-out and reporter mouse lines), the strong preliminary results already obtained, and the leading expertise of the coordinator and his team on IL-33 (20 original publications including 4 papers as senior author in the Top 1% Immunology).