1. Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages
- Author
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Verena M. Link, Ronald M. Evans, Dawn Z Eichenfield, Richard L. Gallo, David Gosselin, Han Cho, Nathanael J. Spann, Christopher K. Glass, Jenhan Tao, Hanna P. Lesch, Ty D. Troutman, Jun Muto, and Michael T. Lam
- Subjects
0301 basic medicine ,Mouse ,Cytoplasmic and Nuclear ,Receptors, Cytoplasmic and Nuclear ,wound healing ,chemistry.chemical_compound ,Mice ,Group D ,Receptors ,Macrophage ,Biology (General) ,genes ,skin and connective tissue diseases ,Rev-erb ,Skin ,General Neuroscience ,General Medicine ,Cell biology ,Genes and Chromosomes ,Medicine ,Signal transduction ,Research Article ,Signal Transduction ,Member 1 ,chromosomes ,Nuclear Receptor Subfamily 1 ,NF-E2-Related Factor 2 ,QH301-705.5 ,1.1 Normal biological development and functioning ,Science ,Macrophage polarization ,macrophage ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Underpinning research ,Genetics ,Animals ,Smad3 Protein ,Enhancer ,Interleukin 4 ,mouse ,Wound Healing ,General Immunology and Microbiology ,epigenetics ,Inflammatory and immune system ,Macrophages ,NF-kappa B p50 Subunit ,NF-κB ,Repressor Proteins ,body regions ,030104 developmental biology ,chemistry ,Nuclear receptor ,Nuclear Receptor Subfamily 1, Group D, Member 1 ,Immunology ,Biochemistry and Cell Biology ,enhancer ,Wound healing - Abstract
Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFβ, and damage-associated molecular patterns (DAMPS). Unexpectedly, a complex damage signal promotes co-localization of NF-κB, Smad3, and Nrf2 at Rev-erb-sensitive enhancers and drives expression of genes characteristic of multiple polarization states in the same cells. Rev-erb-sensitive enhancers thereby integrate multiple damage-activated signaling pathways to promote a wound repair phenotype. DOI: http://dx.doi.org/10.7554/eLife.13024.001
- Published
- 2016