Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming

• Published in: Nature communications 2024-10, Vol.15 (1), p.9000-18, Article 9000
• Main Authors: Deochand, Dinesh K., Dacic, Marija, Bale, Michael J., Daman, Andrew W., Chaudhary, Vidyanath, Josefowicz, Steven Z., Oliver, David, Chinenov, Yurii, Rogatsky, Inez
• Format: Article
• Language: English
• Subjects: 38; 38/39; 45; 45/15; 45/77; 45/88; 45/91; 59; 631/250/2502/2170; 631/337/2019; 64/60; 96; Adaptor Proteins, Signal Transducing; Animals; Anti-inflammatory agents; Bone marrow; Chromatin; Colitis; Colitis - chemically induced; Colitis - genetics; Colitis - metabolism; Convergence; Cytokines; Drug development; Epigenomics; Gene expression; Genomics; Genotype & phenotype; Glucocorticoid receptors; Glucocorticoids; Glucocorticoids - pharmacology; GRIP1 protein; Homeostasis; Humanities and Social Sciences; Immunology; Inflammation; Interleukin 4; Interleukin-4 - genetics; Interleukin-4 - metabolism; KLF4 protein; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Ligands; Macrophages; Macrophages - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phagocytes; Phagocytosis; Phenotypes; Receptors; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Science; Science (multidisciplinary); Transcription factors; Transcriptome; Transcriptomes; Transcriptomics; Wound healing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52942-x

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2 IL4 ). Glucocorticoids (GC), 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 glucocorticoid 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. IL4 and glucocorticoids elicit a homeostatic phenotype in macrophages. Here the authors show that these disparate stimuli yield converging epigenomic and transcriptomic changes, enacted by transcription factors KLF4 and the glucocorticoid receptor, and integrated by their shared coregulator GRIP1.