Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming [ATAC-seq]

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 (IL4) promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids - widely used anti-inflammatory therapeutics - reportedly impart a similar phenotype (M2GC), however how or to what extent these populations functionally converge is unknown. We show that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the GC receptor (GR), whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, 35% of the shared IL4- vs. GC-elicited transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated M2IL4 and M2GC phagocytic activity in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform GR-targeting drug design.