The Epstein-Barr virus-induced gene 2—Cholesterol 25-hydroxylase axis is essential for the recruitment of mast cell progenitors 2260869

Abstract

Abstract Introduction Basophils, eosinophils, and mast cells (MCs) are granulocytes that expand in the airways during type 2 inflammation (T2I)-associated diseases, where they are thought to play a major role in disease pathobiology. While the chemotactic signals recruiting basophils and eosinophils to inflamed tissues are well characterized, the signals directing MC progenitor (MCp) recruitment remain unknown. Methods We conducted single-cell RNA sequencing on flow-sorted MCps and pulmonary endothelial cells, cross-referencing MCp chemokine receptor and endothelial ligand expression to define a series of candidate signals. In addition, we adapted an approach in which mice were intravenously injected with FITC-labeled anti-CD45 to distinguish immune cells within the vasculature from those within the lung parenchyma, thereby tracking the dynamics of MCp recruitment following HDM challenge. Results Mouse MCps displayed high expression of Gpr183, encoding the Epstein-Barr virus-induced gene 2 (EBI2), while pulmonary endothelial cells highly expressed cholesterol 25-hydroxylase (Ch25h), the enzyme responsible for generating EBI2 ligands. These transcriptional profiles were validated in publicly available human scRNA-seq datasets. In wild-type mice, MCps rapidly entered and matured within the lung parenchyma following allergen exposure. In contrast, MCp recruitment to the lung parenchyma was abolished in both Vav1Cre; EBI2FL/FL (Mice with hematopoietic cell—specific deletion of EBI2) mice and Ch25h-/- mice. Conclusion Our findings suggest a key role for the EBI2-Ch25h axis in directing MCp recruitment during T2I. Funding Source NIAID Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)