Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming.
Dinesh K DeochandMarija DacicMichael J BaleAndrew W DamanSteven Zvi JosefowiczDavid OliverYurii ChinenovInez RogatskyPublished in: bioRxiv : the preprint server for biology (2024)
Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2 IL4 ). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2 GC ), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2 IL4 and M2 GC 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, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2 IL4 :M2 GC -shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations 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 anti-inflammatory drug design.
Keyphrases
- genome wide
- anti inflammatory
- single cell
- adipose tissue
- gene expression
- transcription factor
- dna methylation
- gas chromatography
- small molecule
- quality improvement
- copy number
- dna damage
- emergency department
- peripheral blood
- binding protein
- risk assessment
- high resolution
- climate change
- network analysis
- heat shock protein
- liquid chromatography
- solid phase extraction