Basic—Liver, Pancreas, and Biliary TractToll-Like Receptor 9 Promotes Steatohepatitis by Induction of Interleukin-1β in Mice
Section snippets
Animals
Wild-type (WT) C57BL/6 mice and IL-1 receptor (IL-1R)−/− mice were purchased from Jackson Laboratories (Bar Harbor, ME). TLR9−/− and MyD88−/− mice backcrossed at least 10 generations onto the C57BL/6 background were a gift from Dr Akira (Osaka University, Japan).12, 18 These null mice exhibited similar hepatobiliary phenotypes and hepatic lipid contents when fed standard laboratory chow (Supplementary Table 1). Male mice were divided into 3 groups at 8 weeks old; standard chow group (PicoLab
TLR9 Signaling Induces Steatohepatitis and Fibrosis
We investigated the contribution of TLR9 in a murine model of NASH. WT and TLR9−/− mice were fed a CDAA or control CSAA diet for 22 weeks. WT mice had marked lipid accumulation with inflammatory cell infiltration, hepatocyte death, and liver fibrosis (Figure 1A–C;Supplementary Figure 1) after CDAA diet feeding. In contrast, TLR9−/− mice had a significant reduction of steatosis, inflammation, and fibrosis compared with WT mice (Figure 1A–C). No significant differences were observed in food
Discussion
The present study shows that steatohepatitis is diminished in TLR9−/−, IL-1R−/−, and MyD88−/− mice. Kupffer cells, but not hepatocytes and HSCs, respond to TLR9 ligands to produce IL-1β. This IL-1β induces lipid accumulation and cell death in hepatocytes and the expression of fibrogenic mediators in HSCs, resulting in steatosis, hepatocyte injury, and fibrosis (Figure 7B).
Two possible mechanisms activate innate immune systems in NASH. First, translocated bacteria and their products activate the
Acknowledgments
The authors thank Dr Shizuo Akira (Osaka University, Japan) for the generous gift of TLR9−/− and MyD88−/− mice and Dr Katsumi Miyai (Department of Pathology at UCSD), Dr Wuqiang Fan, Dr Saswata Talukdar, Rie Seki, and Karin Diggle (Department of Medicine at UCSD) for excellent technical assistance.
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Conflicts of interest The authors disclose no conflicts.
Funding This study was supported by a Liver Scholar Award from the American Association for the Study of Liver Diseases/American Liver Foundation and by a pilot project from the Southern California Research Center for ALPD and Cirrhosis (P50 AA11999) funded by NIAAA (both to E.S.), NIH grants 5R01GM041804 and 5R01DK072237 (D.A.B.), and Takeda Science Foundation (K.M.).