title: M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.
abstract: Alcoholic and nonalcoholic fatty liver disease (ALD and NAFLD) are the predominant causes of liver-related mortality in Western countries. We have shown that limiting classical (M1) Kupffer cell (KC) polarization reduces alcohol-induced liver injury. Herein, we investigated whether favoring alternatively activated M2 KCs may protect against ALD and NAFLD. Ongoing alcohol drinkers and morbidly obese patients, with minimal hepatic injury and steatosis, displayed higher hepatic expression of M2 genes, as compared to patients with more severe liver lesions; individuals with limited liver lesions showed negligible hepatocyte apoptosis but significant macrophage apoptosis. Experiments in mouse models of ALD or NAFLD further showed that BALB/c or resveratrol-treated mice fed alcohol or a high-fat diet displayed preponderant M2 KC polarization, M1 KC apoptosis, and resistance to hepatocyte steatosis and apoptosis, as compared to control C57BL6/J mice. In vitro experiments in isolated KC, peritoneal, and Raw264.7 macrophages demonstrated that M1 macrophage apoptosis was promoted by conditioned medium from macrophages polarized into an M2 phenotype by either interleukin (IL)4, resveratrol, or adiponectin. Mechanistically, IL10 released from M2 cells promoted M1 death, and anti-IL10 antibodies blunted the proapoptic effects of M2-conditioned media. IL10 secreted by M2 KCs promoted selective M1 death by a mechanism involving activation of arginase in high inducible nitric oxide synthase-expressing M1 KCs. In alcohol-exposed mice, neutralization of IL10 impaired M1 apoptosis.
  
  
  CONCLUSIONS
  These data uncover a novel mechanism regulating the M1/M2 balance that relies on apoptotic effects of M2 KCs towards their M1 counterparts. They suggest that promoting M2-induced M1 KC apoptosis might prove a relevant strategy to limit alcohol- and high fat-induced inflammation and hepatocyte injury.
authors.affiliation: INSERM, U955, Team 17, Créteil, France; Université Paris-Est, UMR_S955, UPEC, Créteil, France.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Wan
authors.forename: Merieme
authors.initials: M
authors.lastname: Benkdane
authors.forename: Fatima
authors.initials: F
authors.lastname: Teixeira-Clerc
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bonnafous
authors.forename: Alexandre
authors.initials: A
authors.lastname: Louvet
authors.forename: Fouad
authors.initials: F
authors.lastname: Lafdil
authors.forename: Françoise
authors.initials: F
authors.lastname: Pecker
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.forename: Ariane
authors.initials: A
authors.lastname: Mallat
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
authors.forename: Catherine
authors.initials: C
authors.lastname: Pavoine
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001119:Arginase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D059305:Diet, High-Fat; D004789:Enzyme Activation; D000431:Ethanol; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009767:Obesity, Morbid / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D000077185:Resveratrol; D013267:Stilbenes
chemical_list: D015415:Biomarkers; C508609:IL10 protein, human; D013267:Stilbenes; D016753:Interleukin-10; D000431:Ethanol; D001119:Arginase; D000077185:Resveratrol