Nuclear receptors as metabolic relays of ILC2-mediated immune responses

• Applicant: Professor Christoph Wilhelm, Ph.D.
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470987585

Innate lymphoid cells (ILC) serve the major task of protection and maintenance of the tissue barrier. However, chronic activation of ILC can promote inflammation and contribute to inflammatory disorders affecting barrier sites. We could previously show that the protective function of intestinal type 2 ILC (ILC2) in helminth infections critically depends on fatty acid FA metabolism and FAO, while glucose is dispensable. Investigating the metabolic pathways controlling the function of pathogenic ILC2 in airway inflammation we discovered that the acquisition of external glucose and lipids for proliferation as a prerequisite for chronic activation. Skewing the host towards catabolic lipid metabolism and fatty acid oxidation (FAO) by feeding mice a ketogenic diet ablated ILC2-mediated airway inflammation. In this proposal we aim to identify the molecular relay regulating the metabolic switch between protective and pathogenic ILC2 responses. We propose that such relays are represented by nuclear receptors regulated by the dietary status of the host and controlling cell intrinsic metabolism in ILC2. To investigate our hypothesis we will search for candidate nuclear receptors upregulated in ketogenic diet and in control of catabolic FA metabolism, we found to prevent the induction of pathogenic ILC2 responses. We will test our candidate(s) to metabolically control protective intestinal ILC2 in the context of helminth infection and prevent the development of pathogenic ILC2 in airway inflammation. Overall, investigating and identifying mechanisms mediating a switch from pathogenic to protective ILC2 responses offers a previously unexplored approach to treat chronic inflammation. Thus with our research we aim to the tackle one major societal challenge, the dramatic increase in chronic inflammatory disorders in the Western World and to identify novel targets for therapeutic intervention.

• DFG Programme: Research Grants