Toll-like receptor 7-mediated type I interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis

Roh, Yoon Seok; Park, Surim; Kim, Jong Won; Lim, Chae Woong; Seki, Ekihiro; Kim, Bumseok

doi:10.1002/hep.26981

Cited by 54 publications

(58 citation statements)

References 44 publications

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“…5J) and augmented expression of Acta2 and Col1a2 (Fig. 5K) compared with WT mice, which is consistent with the previously reported anti-fibrotic role of type I IFNs (23,24). Taken together, these data implied that IRF3, but not IRF7 or type I 4 .…”

Section: Induces Early Association Of Irf3 With Sting In the Ersupporting

confidence: 91%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

124

119

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Edited by Jeffrey PessinFibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic CCl 4 administration to WT and IRF3-, Toll/ Interleukin-1R (TIR) domain-containing adapter-inducing interferon-␤ (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute CCl 4 administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl 4 . Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl 4 . In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the proapoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.

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Section: Induces Early Association Of Irf3 With Sting In the Ersupporting

confidence: 91%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

124

119

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“…Innate adaptive immune responses induced by various cytokines follow the interaction of TLRs with each specific ligand11. Recent studies about liver diseases and TLRs have suggested various possible mechanisms related to pathophysiological change due to immune responses121314. TLR7 is a commonly identified that response to viruses, bacteria, and other TLR7 agonists15.…”

mentioning

confidence: 99%

“…TLR7 is a commonly identified that response to viruses, bacteria, and other TLR7 agonists15. Although the role of TLR7 signaling in liver fibrosis has been demonstrated14, the role of TLR7 signaling in the progression of NAFLD has not been elucidated. Therefore, we investigated TLR7 and the “two-hit” hypothesis to provide mechanistic insight into this complex and dynamic disease.…”

mentioning

confidence: 99%

Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

Kim

Park

Kim

et al. 2016

Sci Rep

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Recently, a possible link between toll-like receptor 7 (TLR7) and liver disease was suggested, although it was limited to fibrosis. Based on this report, we investigated whether TLR7 has a pivotal role in non-alcoholic fatty liver disease (NAFLD). The TLR7 signaling pathway, which is activated by imiquimod (TLR7 ligand) naturally, induced autophagy and released insulin-like growth factor 1 (IGF-1) into medium from hepatocytes. Lipid accumulation induced by unsaturated fatty acid (UFA; arachidonic acid:oleic acid = 1:1) in hepatocytes, was attenuated in TLR7 and autophagy activation. Interestingly, TLR7 activation attenuated UFA-induced lipid peroxidation products, such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE). To clarify a possible pathway between TLR7 and lipid peroxidation, we treated hepatocytes with MDA and 4-HNE. MDA and 4-HNE induced 2-folds lipid accumulation in UFA-treated hepatocytes via blockade of the TLR7 signaling pathway’s IGF-1 release compared to only UFA-treated hepatocytes. In vivo experiments carried out with TLR7 knockout mice produced results consistent with in vitro experiments. In conclusion, TLR7 prevents progression of NAFLD via induced autophagy and released IGF-1 from liver. These findings suggest a new therapeutic strategy for the treatment of NAFLD.

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“…11 In the liver, IFNAR1 signalling protects against fibrosis, ischaemia/reperfusion and toll-like-receptor-induced injury. [12][13][14][15] Data on the role of type I IFNs in metabolic diseases remain scarce.…”

Section: Significance Of This Studymentioning

confidence: 99%

Adipose type I interferon signalling protects against metabolic dysfunction

Adolph¹,

Wieser²,

Grander³

et al. 2017

Journal of Hepatology

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Objective Low-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD. Design We determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and β) receptor 1 (Ifnar1) in hepatocytes (Ifnar1

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Toll-like receptor 7-mediated type I interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis

Cited by 54 publications

References 44 publications

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

Adipose type I interferon signalling protects against metabolic dysfunction

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