Descripción del proyecto
El papel de los metabolitos en la función de los macrófagos
Se ha descubierto que los metabolitos desempeñan funciones clave en la regulación de las respuestas inmunitarias que van más allá de su participación en el metabolismo energético y los procesos biosintéticos. El proyecto Metabinnate, financiado con fondos europeos, se propone estudiar el papel de diferentes metabolitos con propiedades proinflamatorias y antiinflamatorias conocidas similares a las de las citocinas. Sus investigadores determinarán la forma en la que la reprogramación metabólica controla la activación y la función de los macrófagos, así como la regulación dinámica de estos metabolitos concretos. El proyecto no solo proporcionara conocimientos básicos sobre la interacción entre el metabolismo y el sistema inmunitario, sino que además podría ayudar a identificar dianas nuevas para la modulación inmunitaria como estrategia terapéutica contra las enfermedades inflamatorias.
Objetivo
The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
D02 CX56 DUBLIN 2
Irlanda