Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production.
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.


CONCLUSIONS
Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment.


CONCLUSIONS
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.
Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.
Annie-Carole
AC
Tosello-Trampont
Susan G
SG
Landes
Virginia
V
Nguyen
Tatiana I
TI
Novobrantseva
Young S
YS
Hahn
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D002794:Choline / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007728:Kupffer Cells / Q000276:immunology*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D065626:Non-alcoholic Fatty Liver Disease; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine; D002794:Choline