A cortisol-driven gene expression signature from circulating monocytes and neutrophils during severe inflammation

Abstract

AbstractBackgroundGlucocorticoids are used as anti-inflammatory and immunosuppressive drugs in the treatment of many inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), but their use in treatment of severe inflammation in sepsis and shock is controversial. This is at least in part caused by the lack of information regarding responding cell types and the genes which are the targets of glucocorticoidsin vivo. Here, we aim to get an overview of glucocorticoid regulated genes in blood cells and to describe their expression in health, mild and severe inflammation depending on cell type.Methods and FindingsWe used 2 different sets of cortisol induced query genes in a gene expression correlation search of 375+ blood based gene transcription datasets to obtain 2 gene signatures of GC induction, either in the relative absence or in the presence of severe inflammation. Additional searches provided gene expression correlation profiles for separate immune cells and control tissues. Many well known GC target genes were recovered, as well as candidate GC regulated genes, which were further tested for upregulation by GCin vitroin different immune cells. Genes from GC signature 1, present in the relative absence of severe inflammation, and gene markers for cell type and inflammation were evaluated for expression correlation characteristics in a meta analysis of 62 datasets exluding severe inflammation, allowing delineation of a core group of GC induced genes including TSC22D3 and DDIT4. Several genes from this core group were highly upregulated in whole blood by circadian GC, and by GC treatment of healthy people, and suitable for combined use as biomarker of GC action, in the absence of severe inflammation. GC signature 2, present in severe inflammation, originated from gene expression in neutrophils and monocytes, as determined by correlation analysis using 38 datasets on severe inflammation, such as sepsis and trauma, and from gene expression profiles of isolated blood cells from sepsis patients. Genes expressed specifically in monocytes included VSIG4 and ADAMTS2, while genes such as OLAH and ARG1 were preferentially expressed in neutrophils, or expressed in both cell types such as CD163. GC driven signature 2 genes expressed in monocytes, included several markers for alternatively activated macrophages, that were strongly upregulated in severe inflammation. GC signature 2 was present in sepsis, trauma, and ARDS, and found in many other inflammatory diseases such as Kawasaki disease. The gene signature for cortisol induction in severe systemic inflammation might depend on elevated blood cortisol levels and/or the appearance of the distinct neutrophils and monocytes populations as seen in severe inflammation. This points to endogenous cortisol as an important factor for immunosuppressionin vivo.ConclusionWe present a large number of cortisol regulated genes in different blood cells, obtained by transcriptomic meta-analysis, including gene markers that will be potentially useful for monitoring cortisol action in severe inflammation at the cellular level. We further demonstrate that gene induction by GCs in monocytes and neutrophils, associated with severe inflammation, is frequently present in many different inflammatory illnesses.