Mepolizumab Modifies Blood Eosinophil Proteome and Transcriptome in Severe Eosinophilic Asthma

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BACKGROUND: Mepolizumab, an anti-IL5 monoclonal antibody, effectively reduces exacerbations and improves disease control in severe eosinophilic asthma (SEA). While this treatment rapidly decreases blood eosinophil counts, some patients continue to experience asthma symptoms, suggesting that other features beyond eosinophil number contribute to disease persistence. In this work, we aim to characterize the molecular and functional signature of circulating eosinophils in SEA in response to mepolizumab therapy. METHODS: We performed proteomic (LC-MS/MS) and targeted transcriptomic (Nanostring) analyses on isolated blood eosinophils from healthy individuals and SEA patients at baseline and after 4, 16 and 32 weeks of treatment with mepolizumab. Western blot was used to validate selected genes and proteins. RESULTS: Eosinophils from healthy donors and post-treatment SEA patients exhibit lower levels of proteins related to cytoskeleton (e.g., GSN, DBNL, ARPC2 and ARPC3), suggesting a lower potential for migration and tissue extravasation. Several proteins (e.g., EPX and NCF2) and genes (e.g., CCL23 and SOCS3) directly involved in eosinophil effector functions, including ROS generation and degranulation, were significantly downregulated after mepolizumab treatment. The downregulation of GSN (actin-binding protein), NCF2 (subunit of the NADPH oxidase complex) and EPX (eosinophil-specific granule protein), was further validated by western blot. CONCLUSIONS: Our multi-omic analysis suggests that mepolizumab reduces the migratory capacity and effector-related molecular signatures of circulating eosinophils in SEA patients. Selected proteins, including GSN, NCF2 and EPX, may serve as candidate biomarkers for monitoring response to therapy.

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