The importance of lipid metabolism for the maintenance of pathogenic ILC2 responses

• Applicant: Professor Christoph Wilhelm, Ph.D.
• Subject Area: Immunology
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320380384

Over the last decades the epidemiology of immune diseases has changed considerably in the Western World. The gradual eradication of many infectious diseases coincides with an increase of chronic inflammatory conditions including asthma and Crohn’s disease. The vast majority of chronic diseases cannot be cured and current treatment strategies predominately target the acute immune response. However, reactivation of long-lived memory immune cells may cause recurrent flares resulting in chronic inflammation. Thus, a better understanding of the factors promoting longevity of immune cells may guide measures of prevention and cures. The major function of innate lymphoid cells (ILC) is the protection and maintenance of the tissue barrier. However, chronic activation of a specific subtype of ILC type II (ILC2) is a major driver of asthma. In an effort to identify metabolic pathways active in pathogenic ILC2 to treat allergen-driven airway inflammation we found that externally acquired lipids drive proliferation and chronic activation of ILC2. Externally acquired fatty acids must be transiently stored in lipid droplets to prevent lipotoxicity and the increased lipid uptake and storage is controlled by the overall availability of glucose. We further discovered that feeding mice a ketogenic diet and thus restricting the availability of dietary glucose largely ablated ILC2-mediated airway inflammation by impairing both glucose and fatty acid metabolism and the formation of lipid droplets in ILC2. Strikingly, storage of lipids and subsequent energy generation through oxidation of fatty acids is a general feature of long-lived memory T cells and essential for their maintenance and survival. Thus, we propose that increased acquisition of lipids in the context of allergen-driven airway inflammation is an important prerequisite facilitating the long-term maintenance of ‘memory-like’ ILC2 responses. We hypothesize that the maintenance and survival of pathogenic ILC2 critically depends on the capacity of ILC2 to acquire, store and utilize external lipids and propose that targeting lipid metabolism in ILC2 represents an unexplored approach to treat established chronic airway inflammation. To address these questions we will investigate a) the metabolic regulation of memory-like ILC2 responses and b) test the importance of IL-9 to induce a metabolic program tailored towards the long-term survival of ILC2. Further, we will test c) the function of lipid metabolism for the long-term maintenance of pathogenic ILC2 responses and d) investigate the efficacy of ketogenic diet or vitamin A deficient diets to target the metabolic maintenance of established chronic airway inflammation. Overall, investigating and identifying mechanisms of metabolic regulation for the long-term survival and maintenance of ILC2 in airway inflammation offers a previously unexplored approach to encounter the growing public health problem of chronic inflammatory diseases.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells