Toll-Like Receptor 9 Promotes Steatohepatitis by Induction of Interleukin-1β in Mice

By Kouichi Miura, Y. Kodama, S. Inokuchi, B. Schnabl, Tomonori Aoyama, H. Ohnishi, Jerrold M. Olefsky, D. Brenner, E. Seki. Gastroenterology, 2010

703 citations recorded by the source corpus.

BACKGROUND & AIMS Development of nonalcoholic steatohepatitis (NASH) involves the innate immune system and is mediated by Kupffer cells and hepatic stellate cells (HSCs). Toll-like receptor 9 (TLR9) is a pattern recognition receptor that recognizes bacteria-derived cytosine phosphate guanine (CpG)–containing DNA and activates innate immunity. We investigated the role of TLR9 signaling and the inflammatory cytokine interleukin-1β (IL-1β) in steatohepatitis, fibrosis, and insulin resistance. METHODS Wild-type (WT), TLR9−/−, IL-1 receptor (IL-1R)−/−, and MyD88−/− mice were fed a choline-deficient amino acid-defined (CDAA) diet for 22 weeks and then assessed for steatohepatitis, fibrosis, and insulin resistance. Lipid accumulation and cell death were assessed in isolated hepatocytes. Kupffer cells and HSCs were isolated to assess inflammatory and fibrogenic responses, respectively. RESULTS The CDAA diet induced NASH in WT mice, characterized by steatosis, inflammation, fibrosis, and insulin resistance. TLR9−/− mice showed less steatohepatitis and liver fibrosis than WT mice. Among inflammatory cytokines, IL-1β production was suppressed in TLR9−/− mice. Kupffer cells produced IL-1β in response to CpG oligodeoxynucleotide. IL-1β but not CpG-oligodeoxynucleotides, increased lipid accumulation in hepatocytes. Lipid accumulation in hepatocytes led to nuclear factor-κB inactivation, resulting in cell death in response to IL-1β. IL-1β induced fibrogenic responses in HSCs, including secretion of tissue inhibitor of metalloproteinase-1. IL-1R−/− mice had reduced steatohepatitis and fibrosis, compared with WT mice. Mice deficient in MyD88, an adaptor molecule for TLR9 and IL-1R signaling, also had reduced steatohepatitis and fibrosis. TLR9−/−, IL-1R−/−, and MyD88−/− mice had less insulin resistance than WT mice on the CDAA diet. CONCLUSIONS In a mouse model of NASH, TLR9 signaling induces production of IL-1β by Kupffer cells, leading to steatosis, inflammation, and fibrosis.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/da463ca2b3d2079c9e587d0c4aaaa110b766ef8d

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In Epidemiology

1. Robert F. Schwabe
2. M. Pinzani
3. E. Seki
4. D. Brenner
5. Yukinori Koyama
6. E. Tsochatzis
7. G. Szabo
8. E. Buzzetti

In Molecular Biology

1. Robert F. Schwabe
2. D. Brenner
3. Kate Schroder
4. S. Masters
5. J. Petrášek

Citations in the corpus

• NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice (2017, background): “Our data also fail to support a proposed role of IL-1 in contributing to hepatocyte fat deposition in NASH [17,49].”
• IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. (2012, background): “MCP-1 is a chemokine required for the pathogenesis of ALD (24) that, when present in high doses, induces lipid accumulation in hepatocytes (12).”
• The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). (2016, background): “[60] Miura K, Kodama Y, Inokuchi S, et al.”
• The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer (2016, neutral): “Although IL-1 has no or at best a minor role in hepatic fibrogenesis (66, 67), it promotes hepatocarcinogenesis (68).”
• Hepatic Inflammation and Fibrosis: Functional Links and Key Pathways (2015, background): “IL-1b production requires stimulation with TLR ligands as well as a second signal, such as muramyl dipeptide–mediated NOD-like receptor (NLR) stimulation or adenosine triphosphate (ATP)-mediated P2X7 stimulation, to induce both up-regulation of Ilb transcription and subsequent processing of IL-1b pr”
• Liver inflammation and fibrosis. (2017, background): “Furthermore, in NASH, DAMPs from injured hepatocytes activate the inflammasome in Kupffer cells, resulting in release of IL-1β, thereby inducing hepatic stellate cell activation (101).”