Multiomics insights into retinoic acid-mediated regulation of eosinophils in severe asthma.

Abstract

Severe asthma is marked by persistent eosinophilic inflammation, but the role of all-trans retinoic acid (ATRA) in eosinophil homeostasis remains unclear. This study examined the regulatory role of ATRA in eosinophil function in severe asthma. Multiomics analysis (transcriptomics, proteomics, and lipidomics) was conducted on blood eosinophils from healthy participants and patients with severe asthma. The effects of ATRA on eosinophil function were further analyzed by using flow cytometry and quantitative RT-PCR. Transcriptomic profiling of eosinophils from patients with severe asthma revealed a distinct gene expression signature, with upregulation of the genes GGT5, IL2RA, CCL23, and NOD2 and downregulation of SPRY2 and HIC1. This phenotype was driven by type 2 cytokines (IL-5 and IL-4) and muramyl dipeptide but was counterregulated by ATRA. Proteomic analysis showed increased expression of P-selectin glycoprotein ligand-1 in SA-EOS, which was upregulated by type 2 cytokines and downregulated by ATRA. Lipidomic analysis identified dysregulated 15-lipoxygenase metabolism in SA-EOS, with ATRA selectively inhibiting cysteinyl leukotriene metabolism while sparing the 15-lipoxygenase pathway. Multiomics analysis of eosinophils from ATRA-treated healthy participants revealed specific downregulation of IL1RL1 and IL3RA, reducing responsiveness to IL-33 and IL-3 and distinguishing them from IL-5-induced eosinophils. These findings highlight the role of ATRA in maintaining eosinophil homeostasis and counterregulating IL-5-driven activation, thus offering insights into potential therapeutic strategies for severe asthma.