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Abstract Details
Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis
Immunity. 2020 May 1;S1074-7613(20)30159-X. doi: 10.1016/j.immuni.2020.04.001.Online ahead of print.
Jason S Seidman1, Ty D Troutman2, Mashito Sakai1, Anita Gola3, Nathanael J Spann1, Hunter Bennett1, Cassi M Bruni1, Zhengyu Ouyang1, Rick Z Li1, Xiaoli Sun4, BaoChau T Vu1, Martina P Pasillas1, Kaori M Ego1, David Gosselin5, Verena M Link6, Ling-Wa Chong7, Ronald M Evans8, Bonne M Thompson9, Jeffrey G McDonald9, Mojgan Hosseini10, Joseph L Witztum4, Ronald N Germain3, Christopher K Glass11
Author information
1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
2Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: ttroutman@health.ucsd.edu.
3Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 201892, USA.
4Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
5Department of Molecular Medicine, Université Laval, Quebec City, QC, Canada.
6Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Faculty of Biology, Division of Evolutionary Biology, Ludwig-Maximilian University of Munich, Munich, Germany.
7Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
8Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, USA.
9Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA.
10Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
11Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: ckg@ucsd.edu.
Abstract
Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.