Roles, regulation and cooperation of IL-33 and TL1A alarmins in the initiation of allergic airway inflammation – ALARMIN-ALLERGY

Allergic diseases such as asthma, allergic rhinitis (hay fever) and allergic conjunctivitis are common diseases affecting patients from childhood to old age. Severe asthmatic disease may cause a reduced quality of life and lead to premature death. It is therefore essential to better understand the mechanisms that contribute to allergic inflammation of the airways and asthma.

Epithelium-derived cytokines, such as interleukin-33 (IL-33), are major players in allergic inflammation and asthma, as revealed by genome-wide association studies. IL-33, a member of the IL-1 cytokine family, is a chromatin associated nuclear cytokine that we discovered in 2003, as nuclear factor of high endothelial venules (NF-HEV). We demonstrated that IL-33 is abundantly expressed in the nuclei of epithelial cells of barrier tissues, and endothelial cells from blood vessels in various tissues. We showed that IL-33 functions as an alarm signal (or alarmin), rapidly released upon cellular damage to alert tissue-resident immune cells, such as group 2 innate lymphoid cells (ILC2s), that produce high amounts of IL-5 and IL-13 upon IL-33 stimulation.

We recently discovered that TL1A, a member of the TNF superfamily is an epithelial cytokine constitutively expressed in lung epithelium at steady state in both mice and humans that functions as an alarmin, similar to IL-33. We showed that TL1A cooperates with IL-33 for early induction of IL-9-producing ILC2s during the onset of allergic airway inflammation (J Exp Med 2024). After co-stimulation by IL-33 and TL1A, lung ILC2s acquired a transient ‘ILC9’ phenotype, characterized by simultaneous production of large amounts of IL-9, IL-5 and IL-13. We proposed that epithelial alarmins IL-33 and TL1A, and ‘ILC9’ cells functioned together in a potent alarm system activated after a single allergen exposure for initiation of airway inflammation.

The major objectives of the ALARMIN-ALLERGY project are to provide a better understanding of the early mechanisms involved in the initiation of allergic responses in the airways, including the roles and regulation of alarmin cytokines IL-33 and TL1A, two critical inducers of allergic airway inflammation. To reach these objectives, we will use mouse models of allergic airway inflammation and multi-disciplinary approaches (transgenic mouse models, immunological assays, molecular and cellular biology, biochemical and mass spectrometry approaches, high-throughput proteomic analyses).

Based on the complementary scientific and technological expertise of the teams involved (> 20 years of expertise on IL-33; 7 joint-publications by members of the consortium), the tools available and the preliminary results already obtained, we predict that the ALARMIN-ALLERGY project will lead to several important advances/breakthroughs and reveal potential strategies for reducing IL-33- and/or TL1A-mediated allergic inflammation in vivo. The ALARMIN-ALLERGY project will thus contribute to develop fundamental knowledge that could help prevent and treat human allergic diseases.