The Role of GCN2-Dependent Metabolic Stress in Type-2 Inflammation Within the Lung

Abstract

Determining the control mechanisms behind the development of type-1 and type-2 inflammation could hand us the key to treating inflammatory pathologies like asthma, allergy, and cancer. One potential mechanism is the IDO-GCN2 nutrient stress-sensing pathway that has been implicated during pregnancy, bacterial infections, and others. We have determined that during type-2 inflammation IDO is induced and depletes the environment of tryptophan, this lack of tryptophan then activates GCN2. GCN2, especially when activated in the M2 macrophage subset, helps to regulate the cytokine production, cellular infiltrate, antibody production, and T-cell proliferation, activation, and differentiation. These effect culminate into regulating the overall lung pathology. This study suggests a novel type-2 inflammatory control mechanism through the GCN2 signaling pathway, and provides a potential therapeutic target for treatment of type-2 pathologies, like helminth infection, asthma, allergy, and cancers.