BACKGROUND: The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. RESULTS: Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNFα production, chemokine induction, and monocyte recruitment. The silencing of TNFα in myeloid cells reduces NASH progression. CONCLUSION: Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. SIGNIFICANCE: Myeloid cells-targeted silencing of TNFα might be a tenable therapeutic approach. Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1.
BACKGROUND: The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. RESULTS: Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNFα production, chemokine induction, and monocyte recruitment. The silencing of TNFα in myeloid cells reduces NASH progression. CONCLUSION: Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. SIGNIFICANCE: Myeloid cells-targeted silencing of TNFα might be a tenable therapeutic approach. Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1.
Authors: Klaus H W Boeker; Christian I Haberkorn; Dirk Michels; Peer Flemming; Michael P Manns; Ralf Lichtinghagen Journal: Clin Chim Acta Date: 2002-02 Impact factor: 3.786
Authors: K Tomita; G Tamiya; S Ando; K Ohsumi; T Chiyo; A Mizutani; N Kitamura; K Toda; T Kaneko; Y Horie; J-Y Han; S Kato; M Shimoda; Y Oike; M Tomizawa; S Makino; T Ohkura; H Saito; N Kumagai; H Nagata; H Ishii; T Hibi Journal: Gut Date: 2005-09-20 Impact factor: 23.059
Authors: Jaime Poniachik; Attila Csendes; Juan C Díaz; Jorge Rojas; Patricio Burdiles; Fernando Maluenda; Gladys Smok; Ramón Rodrigo; Luis A Videla Journal: Cytokine Date: 2006-03-27 Impact factor: 3.861
Authors: John Willy Haukeland; Jan Kristian Damås; Zbigniew Konopski; Else Marit Løberg; Terese Haaland; Ingeborg Goverud; Peter A Torjesen; Kåre Birkeland; Kristian Bjøro; Pål Aukrust Journal: J Hepatol Date: 2006-03-20 Impact factor: 25.083
Authors: Marcus Mühlbauer; Anja K Bosserhoff; Arndt Hartmann; Wolfgang E Thasler; Thomas S Weiss; Hans Herfarth; Guntram Lock; Jürgen Schölmerich; Claus Hellerbrand Journal: Gastroenterology Date: 2003-10 Impact factor: 22.682
Authors: Amrom E Obstfeld; Eiji Sugaru; Marie Thearle; Anne-Marie Francisco; Constance Gayet; Henry N Ginsberg; Eleanore V Ables; Anthony W Ferrante Journal: Diabetes Date: 2010-01-26 Impact factor: 9.461
Authors: Kyoko Tomita; Ayano Kabashima; Brittany L Freeman; Steven F Bronk; Petra Hirsova; Samar H Ibrahim Journal: J Cell Biochem Date: 2017-05-15 Impact factor: 4.429
Authors: Sofia de Oliveira; Ruth A Houseright; Alyssa L Graves; Netta Golenberg; Benjamin G Korte; Veronika Miskolci; Anna Huttenlocher Journal: J Hepatol Date: 2018-12-18 Impact factor: 25.083
Authors: Simon Ducheix; Maria Carmela Vegliante; Gaetano Villani; Nicola Napoli; Carlo Sabbà; Antonio Moschetta Journal: Cell Mol Life Sci Date: 2016-08-13 Impact factor: 9.261