Defining a novel immune signaling pathway that protects from intestinal inflammation

• Applicant: Dr. Veronika Horn
• Subject Area: Gastroenterology ; Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538613660

Inflammatory bowel disease (IBD) is a group of incurable chronic inflammatory conditions of the gut. Tumor necrosis factor (TNF)-induced inflammation is a hallmark of IBD, and anti-TNF-directed therapies are successful in clinical practice. However, only a subset of patient develops a sustained response and the essential pathways that protect from TNF-induced intestinal damage are incompletely understood. The fundamental focus of this proposal is to comprehensively define a novel mechanism that safeguards the intestine from intestinal inflammation. Group 3 innate lymphoid cells (ILC3s) are abundant in the healthy intestine and regulate tissue homeostasis by orchestrating appropriate responses towards pathogens, microbiota, and dietary antigens. Remarkably, accumulating evidence demonstrates a profound dysregulation and drastically reduction of ILC3 numbers in the intestine of IBD patients. Therefore, modulation of ILC3 numbers or function could be a therapeutic strategy to promote intestinal health. Recently, my host laboratory reported several novel pathways by which ILC3s are essential to protect the intestine from TNF-induced damage. Based these findings, I generated new data that suggest that ILC3s constitutively express machinery to produce a key tissue-protective effector molecule that increased upon interleukin-1 signaling. Furthermore, expression of these key effector molecules by ILC3s limited TNF-production of other intestinal cell types, which could be a novel mechanism by which ILC3 limit intestinal inflammation. However, the role of this pathway in intestinal inflammation is poorly understood, and the clinical importance remains unexplored. Expanding on these exciting preliminary findings and leveraging my physician scientist background, I propose a central hypothesis that production of this key molecule by ILC3s represents a critical checkpoint to limit chronic inflammation and promote its resolution. In this proposal, I will extensively test this hypothesis with numerous cutting-edge approaches, including lineage-specific knockout mice coupled with different models of intestinal inflammation. Furthermore, I will directly test the clinical importance of these findings in intestinal biopsies from IBD patients. Overall, this proposal will provoke a better understanding on how ILC3s protect from intestinal inflammation, as well as how these pathways could be harnessed to improve TNF-directed therapies or to develop new therapeutics for TNF-resistant IBD patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Gregory F. Sonnenberg