title: Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.|Biomedical Sciences Graduate Program, University of California, San Diego, San Diego, United States.
authors.forename: Dawn Z
authors.identifier: 0000-0002-1511-3804
authors.initials: DZ
authors.lastname: Eichenfield
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Ty Dale
authors.identifier: 0000-0001-8925-8080
authors.initials: TD
authors.lastname: Troutman
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.|Department II, Faculty of Biology, Ludwig-Maximilian Universität München, Planegg-Martinsried, Germany.
authors.forename: Verena M
authors.identifier: 0000-0002-3207-312X
authors.initials: VM
authors.lastname: Link
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.|Biomedical Sciences Graduate Program, University of California, San Diego, San Diego, United States.|Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lam
authors.affiliation: Salk Institute for Biological Sciences, La Jolla, United States.
authors.forename: Han
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
authors.forename: David
authors.initials: D
authors.lastname: Gosselin
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Hanna P
authors.initials: HP
authors.lastname: Lesch
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Jenhan
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Dermatology, University of California, San Diego, San Diego, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Muto
authors.affiliation: Department of Dermatology, University of California, San Diego, San Diego, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.affiliation: Salk Institute for Biological Sciences, La Jolla, United States.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.|Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Christopher K
authors.identifier: 0000-0003-4344-3592
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D008264:Macrophages / Q000502:physiology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000293:injuries*; D051900:Smad3 Protein / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D051267:NF-E2-Related Factor 2; D052002:NF-kappa B p50 Subunit; C495636:Nfe2l2 protein, mouse; C498262:Nr1d1 protein, mouse; C499650:Nr1d2 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C073701:Nfkb1 protein, mouse
keywords: Rev-erb; chromosomes; enhancer; epigenetics; genes; macrophage; mouse; wound healing