April 4, 2022

COMMD10 drives macrophages to regenerate the injured liver

The liver has a remarkable ability to renew itself in a process called regeneration- regrowth of liver tissue following partial resection or injury. This is already documented in Greek mythology relating to Prometheus, who stole fire from the gods and granted it to humans. He was punished by being chained to a cliff, and every day an eagle came to peck at his liver. Night after night, the liver would grow back. Immune cells in the liver assist regeneration. The main immune cells responsible for this process are macrophages (from the Greek Makros=large and Phagein= to eat). These cells can swallow (a process called phagocytosis) and serve as “vacuum cleaners” of the immune system due to their critical role in identifying, dismantling and clearing infectious agents, dead cells and debris. During liver disease, macrophages are the first to identify and respond to injury by recruiting other immune cells to aid the healing effort, clearing dead cells and secreting agents that support regeneration. However, if their activity is not well controlled, as often happens in chronic liver disease, they may worsen the damage. Therefore, it is highly important to understand the variables that control the differentiation and inflammatory activity of these cells.

This research need sparked the curiosity of Dr. Chen Varol, Director of the Research Center for Gastrointestinal and Liver Diseases, Dr. Nathan Gluck, Director of the GI Malignancy Service at the Gastroenterology Institute, and Ph.D. student Keren Cohen. Their research recently uncovered that a protein called COMMD10 is essential for the survival of macrophages in the liver as well as in other organs. They also showed that this protein has a significant role in recovery from drug-induced liver injury. They utilized a mouse model based on an overdose of the analgetic drug acetaminophen, which induces extensive death of liver cells (hepatocytes). Deletion of COMMD10 specifically in liver macrophages hampered their ability to clear dead hepatocytes. In addition, it damaged the repression of their inflammatory activity, which caused worsening of liver damage and inhibited regeneration. In the near future, the investigators plan to continue understanding how COMMD10 functions in macrophages and other liver cells during fatty liver disease, liver cirrhosis and liver cancer. Better understanding the mechanism of COMMD10 action will allow development of novel therapies for these diseases, in which macrophages will be redirected towards healing rather than damage.

The scientific paper was recently published in the prestigious journal Cell Reports.  paper link

Keren Cohen,1,2 Odelia Mouhadeb,1,2 Shani Ben Shlomo,1 Marva Langer,1,2 Anat Neumann,1 ‎Noam Erez,1‎
Itay Moshkovits,1,3 Rotem Pelet,1 Daniel J. Kedar,4 Eli Brazowski,1 Martin Guilliams,5,6 Helen S. ‎Goodridge,7‎
Nathan Gluck,1,* and Chen Varol1,2,*‎
‎1 Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, and Sackler ‎School of Medicine, Tel-Aviv University,‎
Tel-Aviv 64239, Israel
‎2 Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv ‎University, Tel-Aviv 69978, Israel
‎3 Internal Medicine T, Sourasky Medical Center, Tel-Aviv 64239, Israel
‎4 Department of Plastic and Reconstructive Surgery, Sourasky Medical Center, Tel-Aviv 64239, ‎Israel
‎5 VIB-UGent Center for Inflammation Research, Ghent, Belgium
‎6 Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
‎7 Board of Governors Regenerative Medicine Institute and Research Division of Immunology, ‎Department of Biomedical Sciences,‎
Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
‎*Corresponding authors ‎

This figure shows liver macrophages (Kupffer cells, red) in their strategic location in the liver, adjacent to hepatocytes (blue), fibroblast stellate cells (yellow) and blood vessels (turquoise).