Glucocorticoids are a mainstay treatment for a number of rheumatic diseases, and yet the mechanisms underlying their immunoregulatory effects remain partially understood. To address this knowledge gap, researchers have developed a pathway-level map of the genomic response of different cell types to glucocorticoids.

Credit: KTSDESIGN/SCIENCE PHOTO LIBRARY

“Within each molecular pathway in this map, we can zoom in to look at the specific genes that are affected,” explains Luis Franco, corresponding author of the study. “Our hope is that this map will enable other investigators to explore the response to glucocorticoids in their cell of interest.”

The researchers began by using RNA sequencing to simultaneously measure the response to glucocorticoids of every gene in the human genome. “We chose to go beyond mixed cells, to study nine specific cell types: four immune (B cells, CD4+ T cells, neutrophils, and monocytes) and five non-immune (osteoblasts, myoblasts, fibroblasts, preadipocytes, and endothelial cells),” explains Franco.

They found that the glucocorticoid-mediated transcriptional response was cell type-dependent. Of the 9,457 genes that were differentially expressed in at least one cell type, nearly half were responsive to treatment in only one cell type, and only 25 genes were responsive in all cell types. Furthermore, the responses of particular genes were cell type-dependent. “These findings suggest that classifying genes as glucocorticoid-induced or glucocorticoid-repressed, as is common in the literature, should only be done in the context of a specific cell type.”

Focusing on B cells, they found that glucocorticoids affect two important pathways: B cell receptor and Toll-like receptor 7 signalling. “Our findings suggest that functional impairment of signalling through these two pathways could be a major reason why glucocorticoids are effective in the treatment of autoimmune diseases”.

the glucocorticoid-mediated transcriptional response was cell type-dependent

“Now that we have a better idea of the ‘normal’ human response to glucocorticoids, our immediate plan is to apply a similar approach to understanding the response in patients with autoimmune diseases,” says Franco. “A better understanding of what glucocorticoids really do should eventually pave the way to equally efficacious but safer therapeutic alternatives.”