Inflammation reshapes epidermal and leukocyte differentiation resulting in altered glucocorticoid responsiveness

Glucocorticoids are widely prescribed anti-inflammatory drugs that act on nearly all cell types due to the ubiquitous expression of the glucocorticoid receptor (GR). While the molecular mechanisms of GR activation have been studied extensively, it is less well understood how GR signaling modulates cell type-specific responses during inflammation. Using the unique attributes of the zebrafish, we performed single-cell RNA sequencing to characterize GR-mediated transcriptional regulation under conditions of wounding-induced inflammation. We found specific cell populations that occurred only under inflammatory conditions within epidermal cells, macrophages and neutrophils. The inflammation-specific subset of epidermal cells showed elevated expression of inflammatory markers, and these cells exhibited a reduced transactivation response to dexamethasone. This reduction in GR activation was also observed in the inflammation-specific subset of macrophages, but not in neutrophils, which retained dexamethasone responsiveness. By correlating the dexamethasone responsiveness with transcriptional coregulator expression, we identified candidate regulatory mechanisms underlying differential GR responsiveness across cell types. Taken together, we provided unique mechanistic insights into cell differentiation during a local inflammatory response and cell type-specific glucocorticoid responsiveness in vivo.