Myeloid Plasticity of Neutrophil Precursors Contributes to Eosinophil Emergency Hematopoiesis

Abstract Eosinophils and neutrophils are heterogenous cells that play diverse roles in homeostasis and inflammation. Tissue eosinophil origins are poorly understood, posing challenges in the functional interpretation of heterogeneous phenotypes. New evidence from our lab shows unexpected hematopoietic plasticity of Ly6G(+)IL-5Rα(+) band-stage neutrophils with potential to contribute to eosinophil lineage. Using flow cytometry and multi-omics approaches in mouse and human tissue samples derived from healthy and allergic conditions, we tested the hypothesis that neutrophil plasticity contributes to eosinophil diversity in inflammation. We found at least two distinct populations of neutrophils at a healthy baseline, one of which expressed classical neutrophils markers (S100A8/9) while the other expressed both neutrophil (MPO, ELANE) and eosinophil-specific (EPX, PRG2) granule proteins, indicating an intermediate hematopoietic state. In human and mouse neutrophils treated with IL-5/G-CSF in vitro, a subset with mixed characteristics acquired eosinophil-specific granular proteins and eosinophil cell surface markers (Siglec8, CCR3). In a mouse asthma model, using scRNA-seq, we found overlap in neutrophils and eosinophils with tissue remodeling functions. We also identified activated neutrophils and eosinophils playing unique roles in inflammation. Our findings implicate eosinophil emergency hematopoiesis driven by neutrophil plasticity as an overlooked process driving persistence of tissue eosinophils in inflammation. Supported by grants from GSK ISS and NIH R01