Cross-tissue single-cell landscape of neutrophil heterogeneity and immunity in health and disease

Abstract Neutrophils, the most abundant leukocytes in human blood, play multifaceted roles in health and disease. They serve as essential components of immune defense against infection while also contribute to pathogenesis in a variety of diseases including cancer and autoimmunity. Many studies have identified functionally diverse neutrophil subsets in specific diseases and used varied nomenclatures. A comprehensive landscape of neutrophil heterogeneity and immunity is not yet fully elucidated. To fully characterize neutrophils in health and disease, we collected and curated the transcriptomic profiles of 910,791 neutrophils from over 14 tissues across 24 single-cell RNA-seq datasets to generate a neutrophil single-cell compendium, which covered multiple diseases including viral and bacterial infection, cancer, diabetes, cardiovascular disease, and autoimmune diseases. We identified multiple neutrophil subsets exhibiting distinct heterogeneity along the development trajectories from pro- and immature neutrophils to mature neutrophils. We focused on pro- and immature neutrophils as well as mature neutrophil subsets displaying immunosuppressive transcriptional programs shared across diseases such as cancer and infections. We also inferred the cell-cell interaction between neutrophils and other immune cells in various disease contexts. Together, our systematic meta-analysis of neutrophils supported the development of neutrophil-based diagnostic tools and immunotherapy strategies.