Attenuation of CCl<sub>4</sub>-induced hepatic fibrosis by GdCl<sub>3</sub>treatment or dietary glycine

Rivera, Chantal A.; Bradford, Blair U.; Hunt, Kelly J.; Adachi, Yoshifumi; Schrum, Laura W.; Koop, Dennis R.; Burchardt, Elmar R.; Rippe, Richard A.; Thurman, Ronald G.

doi:10.1152/ajpgi.2001.281.1.g200

Cited by 151 publications

(140 citation statements)

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“…Several studies have demonstrated that Kupffer cells play a critical role in various forms of liver injury via paracrine interactions with hepatocytes. For example, depletion or inactivation of Kupffer cells diminished injury and fibrosis due to chronic carbon tetrachloride exposure early as well as early alcoholic steatohepatitis (ASH) (16,17,23), without affecting ethanol metabolism (24).…”

Section: Discussionmentioning

confidence: 99%

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Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

Rivera

Adegboyega

Rooijen

et al. 2007

Journal of Hepatology

612

509

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BACKGROUND/AIMS-Studies in animal models and humans suggest a link between endotoxemia and non-alcoholic steatohepatitis. Since Kupffer cells are responsible for clearing endotoxin and are activated via endotoxin interaction with Toll-like receptor 4 (TLR-4), we examined the relationship between hepatic TLR-4 expression and Kupffer cell content during the genesis of steatohepatitis.METHODS-Male C57BL/6, C3H/HouJ and TLR-4 mutant C3H/HeJ mice were fed control or methionine/choline-deficient diet (MCDD). In one group of C57BL/6 mice, Kupffer cells were depleted by weekly intravenous injections of clodronate liposomes. After 3 weeks, serum ALT activity and portal endotoxin levels were measured. Real-time PCR was used to examine mRNA expression of TLR-4, TLR-2, CD14, MD-2, TGFβ, TNFα CD36 PPAR-α, liver fatty acid binding protein (L-FABP) and collagen α1.RESULTS-We observed histological evidence typical of steatohepatitis, portal endotoxemia and enhanced TLR-4 expression in wild type mice fed MCDD. In contrast, injury and lipid accumulation markers were significantly lower in TLR-4 mutant mice. Destruction of Kupffer cells with clodronate liposomes blunted histological evidence of steatohepatitis and prevented increases in TLR-4 expression.CONCLUSIONS-These findings demonstrate the importance of TLR-4 signaling and underscore a direct link between TLR-4 and Kupffer cells in the pathogenesis of steatohepatitis.

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Section: Discussionmentioning

confidence: 99%

“…We have shown previously that Kupffer cells also play a causal role in fibrogenesis (17). Hepatic fibrosis may occur simultaneously with hepatitis and is characterized by the overproduction of extracellular matrix proteins such as Collagen type I (26).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

Rivera

Adegboyega

Rooijen

et al. 2007

Journal of Hepatology

612

509

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“…Inflammation triggers liver fibrosis via a signaling event in which liver resident macrophages (Kupffer cells, KC) activate hepatic stellate cells (HSCs) 2 to deposit collagen (1,2). Liver dysfunction results from the fibrotic tissue distorting the liver parenchyma.…”

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confidence: 99%

“…: 508-856-5275; Fax: 508-856-4770; E-mail: gyongyi.szabo@umassmed.edu. 2 The abbreviations used are: HSC, hepatic stellate cell; IRF3, interferon regulatory factor 3; STING, stimulator of interferon genes; ER, endoplasmic reticulum; ␣-SMA, ␣-smooth muscle actin; IFNAR1, type I IFN receptor; TIR, Toll/interleukin-1R; TRIF, TIR domain-containing adapter-inducing interferon-␤; TRAM, TRIF-related adaptor molecule; TBK1, Tank-binding kinase 1; TLR, Toll-like receptor; LMNC, liver mononuclear cell; H&E, hematoxylin and eosin.…”

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confidence: 99%

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

132

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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“…In agreement with this hypothesis, deletion of specific components of the inflammatory response modifies or attenuates the fibrotic scar in vivo. It has been demonstrated that Kupffer cell inactivation, 4 B lymphocyte deficiency, 5 or macrophage depletion 6 result in lower scarring and reduced activation of HSCs.…”

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confidence: 99%

Dual Role of CCR2 in the Constitution and the Resolution of Liver Fibrosis in Mice

Mitchell

Couton

Couty

et al. 2009

The American Journal of Pathology

170

160

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Inflammation has been shown to induce the progression of fibrosis in response to liver injury. Among inflammatory cells, macrophages and lymphocytes play major roles in both the constitution and resolution of liver fibrosis. The chemokine receptor CCR2 is involved in the recruitment of monocytes to injury sites, and it is known to be induced during the progression of fibrosis in humans. However, its specific role during this process has not yet been unveiled. We first demonstrated that, compared with wild-type mice, CCR2 knockout animals presented a delay in liver injury after acute CCl 4 injection, accompanied by a reduction in infiltrating macrophage populations. We then induced fibrosis using repeated injections of CCl 4 and observed a significantly lower level of fibrotic scars at the peak of fibrosis in mutant animals compared with control mice. This diminished fibrosis was associated with a reduction in F4/ 80 ؉ CD11b ؉ and CD11c ؉ populations at the sites of injury. Subsequent analysis of the kinetics of the resolution of fibrosis showed that fibrosis rapidly regressed in wild-type, but not in CCR2 ؊/؊ mice. The persistence of hepatic injury in mutant animals was correlated with sustained tissue inhibitor of metalloproteinase-1 mRNA expression levels and a reduction in matrix metalloproteinase-2 and matrix metalloproteinase-13 expression levels. In conclusion, these findings underline the role of the CCR2 signaling pathway in both the constitution and resolution of liver fibrotic scars.

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Attenuation of CCl₄-induced hepatic fibrosis by GdCl₃treatment or dietary glycine

Cited by 151 publications

References 43 publications

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

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

Dual Role of CCR2 in the Constitution and the Resolution of Liver Fibrosis in Mice

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Attenuation of CCl4-induced hepatic fibrosis by GdCl3treatment or dietary glycine

Cited by 151 publications

References 43 publications

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

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

Dual Role of CCR2 in the Constitution and the Resolution of Liver Fibrosis in Mice

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Attenuation of CCl₄-induced hepatic fibrosis by GdCl₃treatment or dietary glycine