title: Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis.
abstract: As a cellular degradation mechanism, autophagy exerts crucial and complicated effects on HCC development. Liver non-parenchymal cells, including hepatic resident macrophage Kupffer cells, also play important roles in this process. However, most associated studies have focused on the influence of the autophagy level in hepatic cells and HCC cells, but not liver non-parenchymal cells. Based on our previous study, we confirmed that Atg5 silence in the liver during the preneoplastic stage facilitated liver fibrosis, inflammation and, ultimately, tumorigenesis. We further found that autophagy deficiency promotes the production of inflammatory and fibrogenic factors in macrophages. Moreover, Kupffer cell depletion rescued the tumor-promoting effect of autophagy deficiency during the preneoplastic stage. In autophagy-deficient macrophages, mitochondrial ROS mediated inflammation- and fibrosis-promoting effects by increasing IL1α/β production via enhancing NF-κB-associated pathways. Both blocking of mitochondrial ROS and blocking the IL1 receptor stopped the promotion of fibrosis, inflammation and tumorigenesis resulting from Atg5 knockdown during the preneoplastic stage. In conclusion, autophagy-deficient Kupffer cells promote liver fibrosis, inflammation and, finally, hepatocarcinogenesis during the preneoplastic stage by enhancing mitochondrial ROS- NF-κB-IL1α/β pathways.
authors.affiliation: Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Xu
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Han
authors.affiliation: Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Chenlei
authors.initials: C
authors.lastname: Cai
authors.affiliation: Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: yanglq_rj@yeah.net.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China. Electronic address: Weilixin_smmu@163.com.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D001343:Autophagy; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D053582:Interleukin-1alpha / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008103:Liver Cirrhosis; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C508584:IL1A protein, human; D053582:Interleukin-1alpha; D016328:NF-kappa B
keywords: Autophagy; Fibrosis; IL1; Inflammation; Kupffer cells