Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming
Abstract Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids (GC), widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such dispa...
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| Format: | Article |
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52942-x |
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| author | Dinesh K. Deochand Marija Dacic Michael J. Bale Andrew W. Daman Vidyanath Chaudhary Steven Z. Josefowicz David Oliver Yurii Chinenov Inez Rogatsky |
| author_facet | Dinesh K. Deochand Marija Dacic Michael J. Bale Andrew W. Daman Vidyanath Chaudhary Steven Z. Josefowicz David Oliver Yurii Chinenov Inez Rogatsky |
| author_sort | Dinesh K. Deochand |
| collection | DOAJ |
| description | Abstract Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids (GC), widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics 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 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 M2IL4:M2GC-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. |
| format | Article |
| id | doaj-art-e001cea56d514630ba8df70cb5e572f3 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e001cea56d514630ba8df70cb5e572f32025-08-20T02:17:50ZengNature PortfolioNature Communications2041-17232024-10-0115111810.1038/s41467-024-52942-xMechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programmingDinesh K. Deochand0Marija Dacic1Michael J. Bale2Andrew W. Daman3Vidyanath Chaudhary4Steven Z. Josefowicz5David Oliver6Yurii Chinenov7Inez Rogatsky8Hospital for Special Surgery Research Institute, David Z. Rosensweig Genomics CenterHospital for Special Surgery Research Institute, David Z. Rosensweig Genomics CenterDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineHospital for Special Surgery Research Institute, David Z. Rosensweig Genomics CenterDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineHospital for Special Surgery Research Institute, David Z. Rosensweig Genomics CenterHospital for Special Surgery Research Institute, David Z. Rosensweig Genomics CenterHospital for Special Surgery Research Institute, David Z. Rosensweig Genomics CenterAbstract Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids (GC), widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics 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 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 M2IL4:M2GC-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.https://doi.org/10.1038/s41467-024-52942-x |
| spellingShingle | Dinesh K. Deochand Marija Dacic Michael J. Bale Andrew W. Daman Vidyanath Chaudhary Steven Z. Josefowicz David Oliver Yurii Chinenov Inez Rogatsky Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming Nature Communications |
| title | Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming |
| title_full | Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming |
| title_fullStr | Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming |
| title_full_unstemmed | Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming |
| title_short | Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming |
| title_sort | mechanisms of epigenomic and functional convergence between glucocorticoid and il4 driven macrophage programming |
| url | https://doi.org/10.1038/s41467-024-52942-x |
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