Single-cell transcriptome profiling reveals neutrophil heterogeneity and orchestrated maturation during homeostasis and bacterial infection

Abstract

SummaryThe full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function, and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers, and therapeutic targets at single-cell resolution.Graphical AbstractHighlightsA comprehensive single-cell resolution transcriptional landscape of mouse neutrophil maturation and fate decision under steady-state and bacterial infection conditions.The pathogen clearance machinery in neutrophils is continuously and gradually built during neutrophil differentiation, maturation, and aging, driven by both known and uncharacterized transcription factors.The three mature neutrophil subsets in peripheral blood, including a novel ISG-expressing subset, are derived from distinct bone marrow neutrophil precursors.Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall neutrophil heterogeneity.Bacterial infection-induced emergency granulopoiesis is mediated by augmented proliferation of early stage neutrophil progenitors and accelerated post-mitotic maturation.