Single-Cell Transcriptomic Profiling Reveals a Distinct Monocyte MIF/ANXA1 Signature Associated With Poor Responsiveness to ICS.

Abstract

Inhaled corticosteroids (ICSs) are the foundation of asthma management, yet a subset of patients exhibits poor clinical response despite adequate treatment. Understanding the cellular and molecular mechanisms underlying this heterogeneity is essential for developing targeted therapies. We performed single-cell RNA sequencing on peripheral blood mononuclear cells from 6 healthy controls, 6 ICS responders, and 4 ICS poor responders with asthma. We analyzed transcriptional profiles of immune cell subsets, focusing on CD14+ monocytes, and assessed signaling pathways using differential gene expression and receptor-ligand interaction analysis. ICS poor responders exhibited a reduced frequency of circulating CD14+ monocytes and upregulation of chemotaxis-related genes, including CCR1, CCL2, CCL7, and CXCL2. ANXA1 and its receptor FPR2, key regulators of anti-inflammatory responses, were downregulated in poor responders, while MIF and its receptors were upregulated. Receptor-ligand analysis identified T cells as a potential paracrine source of MIF signaling. Our findings highlight MIF-ANXA1 dysregulation in CD14+ monocytes as a key immune signature associated with poor ICS response in asthma.