Multi-omics analysis and systems biology integration identifies the roles of IL-9 in keratinocyte metabolic reprogramming.

Abstract IL-9 producing T cells are present in healthy skin as well as in the cutaneous lesions of inflammatory diseases and cancers. However, the roles of IL-9 in human skin during homeostasis and in the pathogenesis of inflammatory disorders remain obscure. In this study, we examined the roles of IL-9 in metabolic reprogramming of human primary keratinocytes (HPKs). High-throughput quantitative proteomics revealed that IL-9 signalling in HPKs disrupts the electron transport chain (ETC) by downregulating multiple ETC proteins. NMR-based metabolomics demonstrated that IL-9 also reduced the production of tricarboxylic acid (TCA) cycle intermediates in HPKs. Integration of multi-omics data with systems level analysis using the constraint based MitoCore model predicted marked IL-9-dependent effects on central carbohydrate metabolism, particularly in relation to the glycolytic switch. Stable isotope metabolomic and biochemical assays confirmed increased glucose consumption and redirection of metabolic flux towards lactate by IL-9. Functionally, IL-9 inhibited reactive oxygen species (ROS) production by IFNγ and promoted HPK survival by inhibiting apoptosis. In conclusion, our data reveal IL-9 as a master regulator of keratinocyte metabolic reprogramming and survival.