Cytokine-Induced Transcriptional Changes in Human Neutrophils Reveal Immune Regulatory Plasticity

Abstract

Neutrophils are the major cellular constituent of blood leukocytes and play a central role in the inflammatory response, producing an array of destructive molecules and antimicrobial proteases that characterise the cells as front-line defenders of the innate immune system, crucial to host defence. It is now appreciated that neutrophils produce and respond to a variety of inflammatory signals and are able to regulate both the innate and adaptive immune responses. However, the mechanisms by which neutrophils respond to different inflammatory signals to regulate their own function and the functions of other immune cells are incompletely defined. In this study, we performed RNA sequencing with bioinformatics analysis of healthy human neutrophils exposed for 1h to a range of pro-inflammatory cytokines. GM-CSF and TNF induced significant changes in expression in the most transcripts including activation of genes regulating apoptosis and genes encoding cytokines and chemokines that can drive the differentiation and activation of CD4 T cells. Stimulation of neutrophils with G-CSF, IFN, IFN{gamma}, IL-1{beta}, or IL-8 resulted in expression of discrete gene sets and differential activation of signalling pathways including changes in cell adhesion and migration, immune receptor expression, apoptosis, and production of pro-inflammatory prostaglandins. This work defines the differential gene expression patterns in neutrophils exposed to different regulatory cytokines. This is important in both increasing our understanding of the role of neutrophils in driving innate and adaptive immune responses and, importantly, for deconvoluting the neutrophil gene expression signatures observed in inflammatory diseases.