Human neutrophils are a key target of glucocorticoids

Abstract Neutrophils play central roles in immunity and inflammation. Glucocorticoids (GCs) are the cornerstone of anti-inflammatory immunosuppressive therapy. While GCs trigger an acute rise circulating neutrophils, little is known about mechanisms by which modulate neutrophil biology. We studied response 9 primary human cells to vitro treatment with GCs. Surprisingly, neutrophils were transcriptionally most responsive cell type, they express proportionally glucocorticoid receptor (GR) transcripts. Long-read RNA-seq revealed 42 full-length GR transcript isoforms twice as many had been reported previously all other types. At protein level, also have a unique diverse set isoforms. In contrast widely accepted model signaling, binds GC molecules cytoplasm then translocates nucleus, localization almost exclusively nuclear, even absence treatment. To validate our findings vivo, we performed study healthy volunteers, blood collected before serially after infusion. generated pathway-level map transcriptome at baseline The vivo transcriptional was strong that observed vitro, predominance upregulation. Among strongly induced genes several either not expressed, or expressed very low levels, baseline. Some proteins encoded these may putative effects on function, including SAMSN1 ZBTB16. These indicate key target for action.