COMMD10 is critical for Kupffer cell survival and controls Ly6Chi monocyte differentiation and inflammation in the injured liver
Keren Cohen,
Odelia Mouhadeb,
Shani Ben Shlomo,
Marva Langer,
Anat Neumann,
Noam Erez,
Itay Moshkovits,
Rotem Pelet,
Daniel J. Kedar,
Eli Brazowski,
Martin Guilliams,
Helen S. Goodridge,
Nathan Gluck,
Chen Varol
Affiliations
Keren Cohen
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
Odelia Mouhadeb
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
Shani Ben Shlomo
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel
Marva Langer
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
Anat Neumann
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel
Noam Erez
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel
Itay Moshkovits
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; Internal Medicine T, Sourasky Medical Center, Tel-Aviv 64239, Israel
Rotem Pelet
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel
Daniel J. Kedar
Department of Plastic and Reconstructive Surgery, Sourasky Medical Center, Tel-Aviv 64239, Israel
Eli Brazowski
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel
Martin Guilliams
VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
Helen S. Goodridge
Board of Governors Regenerative Medicine Institute and Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Nathan Gluck
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; Corresponding author
Chen Varol
Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; Corresponding author
Summary: Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire “neutrophil-like” and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.