Neutrophil Heterogeneity: Molecules to Cellular Behavior

Neutrophils constitute the largest fraction of total circulating leukocytes in humans and mediate early innate immune responses. Although they are often considered a uniform population of short-lived immune cells, emerging evidence from single-cell RNA sequencing and high-dimensional flow cytometry has revealed that neutrophils are functionally and phenotypically heterogeneous in both healthy and pathological conditions. However, a critical gap is how molecularly defined neutrophil states translate into distinct spatiotemporal behaviors in vivo. This review summarizes our current understanding of the molecular signatures underlying neutrophil heterogeneity and explores the functional in vivo behaviors in various diseases, including cancer, sepsis, and ischemic stroke. We also discuss the potential of intravital imaging to bridge the gap between static molecular profiling and dynamic cellular behavior, offering a comprehensive view of the functional heterogeneity of neutrophils.