Comparative single-cell transcriptome analysis informs early innate immune response in severe human burns

Abstract

Abstract Proper wound healing requires a coordinated time-dependent balance of immune pathways to prevent irreversible systemic damage. Given that innate immune cells are first to mobilize to sites of injury, we hypothesize that neutrophils, macrophages, and their interactions are associated with burn severity. To test this, we employed systems immunology and bioinformatics approaches utilizing single-cell transcriptome (scRNA-Seq) in model organisms and large-scale bulk transcriptome of human burns. To this end, we generated the first to-date scRNA-Seq atlas of 6,671 neutrophils and 12,560 macrophages from a time-course zebrafish tail burn model. Our data unveiled transcriptionally distinct subsets that present different dynamics during the wound healing process. We identified the granularity of IL6-IL6R interactions between macrophages and neutrophils, which impair neutrophil recruitment to sterile thermal injury, making the area vulnerable to microbial invasion and subsequent infection. Furthermore, we generated a comprehensive cross-species reference of neutrophils and macrophages in injury models by integrating publicly available mice scRNA-Seq with our zebrafish data. This reference allows us to deconvolute bulk transcriptome data from different published human cohorts and discover signatures of early innate immune cells associated with burn severity in humans. Our discovery demonstrates the power of using comparative bioinformatics approach to better understand the innate immune system during wound healing. In the future, these advances will guide interventional genomics approaches to identify druggable pathways to optimize burn wound healing in human patients.