M2 kupffer cells promote hepatocyte senescence: an IL-6-dependent protective mechanism against alcoholic liver disease.
Alcoholic liver disease is a predominant cause of liver-related mortality in Western countries. The early steps of alcohol-induced steatosis and liver injury involve several mechanisms, including inflammation and oxidative stress. The inflammatory process is initiated by polarization of Kupffer cells toward a proinflammatory M1 phenotype, and we recently found that promoting anti-inflammatory M2 Kupffer cell polarization protects against alcohol-induced hepatocyte steatosis and apoptosis. Alcohol-induced oxidative stress is a potential trigger of senescence, and senescent cells exhibit characteristic functional resistance to apoptosis. We sought to evaluate induction of hepatocyte senescence as an early protective mechanism against alcoholic liver disease. Combining in vivo and in vitro studies, we show that M2 macrophages trigger hepatocyte senescence and enhance alcohol-induced hepatocyte senescence, as indicated by increased β-galactosidase activity, elevated CDKN1A mRNA expression, and induction of nuclear p21. We identify IL-6 as the mediator of M2-induced hepatocyte senescence. Senescent hepatocytes display characteristic resistance to apoptosis but also to steatosis, thus arguing for an early protective effect against alcoholic liver disease. These findings further suggest that pharmacologic interventions targeting M2 polarization during the early stages of alcoholic liver disease may represent an attractive strategy for the limitation of inflammation, hepatocyte apoptosis, and steatosis.
INSERM, U955, Team 17, Créteil, France; UMR_S955, University of Paris-Est. Créteil, Créteil, France.
Jinghong
J
Wan
INSERM, U955, Team 17, Créteil, France; UMR_S955, University of Paris-Est. Créteil, Créteil, France.
Merieme
M
Benkdane
INSERM, U955, Team 17, Créteil, France; UMR_S955, University of Paris-Est. Créteil, Créteil, France.
Elizabeth
E
Alons
INSERM, U955, Team 17, Créteil, France; UMR_S955, University of Paris-Est. Créteil, Créteil, France; Department of Hepatology and Gastroenterology, AP-HP, Hôpital H. Mondor-A. Chenevier, Créteil, France.
Sophie
S
Lotersztajn
INSERM, U955, Team 17, Créteil, France; UMR_S955, University of Paris-Est. Créteil, Créteil, France. Electronic address: catherine.pavoine@inserm.fr.
Catherine
C
Pavoine
D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C
D015850:Interleukin-6