Human Eosinophils Express a Distinct Gene Expression Program in Response to IL-3 Compared to Common Beta-Chain Cytokines IL-5 and GM-CSF

• Published in: The Journal of immunology (1950) 2019-06, Vol.203 (2), p.329-337
• Main Authors: Nelson, Ryan K., Brickner, Howard, Panwar, Bharat, Suastegui, Ciro Ramirez, de la Mata, Sara Herrera, Liu, Neiman, Diaz, Damaris, Crotty Alexander, Laura E., Ay, Ferhat, Vijayanand, Pandurangan, Seumois, Grégory, Akuthota, Praveen
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1801668

Despite recent advances in asthma management with anti-IL-5 therapies, many patients with eosinophilic asthma remain poorly controlled. IL-3 shares a common beta subunit receptor with both IL-5 and GM-CSF, but through alpha subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3 and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3 or IL-5 for 48 hours. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene co-expression network analysis independently defined modules of genes that are highly co-expressed. GM-CSF, IL-3 and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a pro-inflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly co-expressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the beta-chain receptor cytokines. IL-3 upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies.