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 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
Michael T Lam
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
Han Cho
Salk Institute for Biological Sciences, La Jolla, United States
David Gosselin
Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
Nathanael J Spann
Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
Hanna P Lesch
Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
Jenhan Tao
Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
Jun Muto
Department of Dermatology, University of California, San Diego, San Diego, United States
Richard L Gallo
Department of Dermatology, University of California, San Diego, San Diego, United States
Ronald M Evans
Salk Institute for Biological Sciences, La Jolla, United States
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
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.
