title: Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice.
abstract: OBJECTIVE
  It was reported that alcohol consumption activated the NLRP3 inflammasome in Kupffer cells, leading to mature interleukin (IL)-1β release in alcoholic liver injury; however, how IL-1β promotes liver injury remains unclear.
  
  
  METHODS
  We investigated the role of IL-1β in alcoholic steatohepatitis by using a chronic plus single-binge ethanol consumption mouse model.
  
  
  RESULTS
  Here, liver steatosis was accompanied by notably increased invariant natural killer T (iNKT) cell numbers and activation, and iNKT-deficient Jα18(-/-) mice developed less alcohol-induced steatosis, with reduced liver inflammation and neutrophil infiltration. Kupffer cells and IL-1β were required for the hepatic iNKT accumulation, as either blocking IL-1β signaling with a recombinant IL-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1β in Kupffer cells by nanoparticle-encapsulated siRNA, resulted in inhibited hepatic iNKT cell accumulation and activation, as well as amelioration of alcoholic fatty liver. In addition, IL-1β overexpression in hepatocytes was sufficient to compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1β correlated with elevated expression of the NLRP3 inflammasome components NLRP3, ASC, and cleaved caspase-1 in Kupffer cells from ethanol-exposed wild-type mice. NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells.
  
  
  CONCLUSIONS
  After alcohol-exposure Kupffer cell-derived IL-1β triggered by NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury.
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
authors.forename: Kele
authors.initials: K
authors.lastname: Cui
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
authors.forename: Guoxiu
authors.initials: G
authors.lastname: Yan
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Congfei
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
authors.forename: Rongbin
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
authors.forename: Zhexiong
authors.initials: Z
authors.lastname: Lian
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China. Electronic address: sunr@ustc.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China. Electronic address: tzg@ustc.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020170:Caspase 1
keywords: Alcoholic steatohepatitis; IL-1β; Kupffer cells; NKT cells