哮喘联盟

Abstract

Eosinophils are central immunoregulatory and effector cells in type 2 immunity and play a pivotal role in asthma pathogenesis. However, the metabolic mechanisms that govern eosinophil expansion and activation remain poorly defined. Here, we show that glutamine metabolism is extensively reprogrammed during eosinophil expansion and activation, as revealed by unbiased RNA-seq transcriptomics, liquid chromatography mass spectrometry (LC-MS)-based metabolomics and stable isotope tracing analyses. Through targeted screening, we found that pharmacological inhibition of glutaminase (GLS1) or pan-transaminase activities using CB839 or aminooxyacetic acid (AOA), respectively, attenuates eosinophil expansion potently in vitro. Using transcriptomic, proteomic, and cytokine array analyses, we reveal that glutamine drives a coordinated transcriptional and translational response that supports a pro-inflammatory signature in cytokine-activated eosinophils in vitro, and that this process is dependent on glutaminase and transaminase enzyme activity. Notably, the AOA-induced inhibition of eosinophil activation was reversed completely by supplementation of cells with non-essential amino acids (NEAAs) in vitro, consistent with its lack of efficacy in attenuating airway inflammation in an ovalbumin (OVA)-induced asthma model in vivo. In contrast, CB839 significantly decreased eosinophil infiltration, tissue pathology, and inflammatory cytokine expression in vivo. Together, these findings uncover an essential role for glutamine metabolism in eosinophil biology and identify GLS1 inhibition by CB839 as a promising therapeutic strategy for eosinophilic asthma.