The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection

Wasmuth, Hermann E.; Zaldivar, Mirko Moreno; Berres, Marie‐Luise; Werth, Alexa; Scholten, David; Hillebrandt, S.; Tacke, Frank; Schmitz, Petra; Dahl, Edgar; Wiederholt, T.; Hellerbrand, Claus; Berg, Thomas; Weiskirchen, Ralf; Trautwein, Christian; Lammert, Frank

doi:10.1016/j.jhep.2007.09.008

Cited by 69 publications

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“…52 Regarding fractalkine and fibrosis, CX3CR1 was identified to have a genetic and functional importance in higher stages of liver fibrosis in chronic hepatitis C, and was noticeably upregulated in patients with enhanced renal fibrosis. 21,22 In experimental post-ischemic renal fibrosis, fractalkine and CX3CR1 expression levels were associated with enhanced inflammation and fibrosis, which could be diminished by blocking antibodies to CX3CR1 through the reduction of a-SMA and Collagen-1. 55 In human CP, this interaction appears to be different.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding our presented data, fractalkine does not seem to be directly involved in the fibrogenesis processes in CP, as it was observed in renal and liver fibrosis. 21,22 In all likelihood, it promotes tissue fibrosis indirectly by increasing the mononuclear cell infiltration and not through the activation of hPSCs. This hypothesis is supported by recent reports: (1) Ishida and colleagues 56 showed that CX3CR1 depletion induced a marked reduction in the number of macrophages and in the release of TGF-b1, and observed reduced a-SMA and Collagen-1 depositions in the skin from wounded CX3CR1 À/À mice.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 Recent data show that fractalkine and CX3CR1 are involved in fibrogenesis, and are associated with renal and liver fibrosis. 21,22 Independently from its peripheral pro-inflammatory effects, peripheral nerve damage leads to up-regulation of fractalkine in DRG and consequently to neuropathic pain, with activation of CX3CR1 on spinal microglia being a crucial mechanism for neuronal sensitization. 12,14,23,24 However, also peripherally present are inflammatory mediators such as TNF-a and IL-1, which might contribute to neuropathic pain, if given access to the peripheral nerve through intraneural injection 25 or peri-sciatic-zymosan-induced inflammation.…”

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confidence: 99%

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Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n ¼ 61) and normal pancreas (NP, n ¼ 21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and a-smooth muscle actin (a-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and a-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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“…Expression of chemokine genes, CCL7 (MCP-3) and CX3CR1, was upregulated to approximately 2.0-fold in NS5A-Tg mice. Importantly, CCL7 has been implicated with portal inflammation in liver disease (49) while CX3CR1 is involved in liver fibrosis due to chronic HCV infection (51).…”

Section: Fig 2 Liver Specimens From Day 7 Ad-infected Ntg and Ns5a-mentioning

confidence: 99%

Inhibition of Intrahepatic Gamma Interferon Production by Hepatitis C Virus Nonstructural Protein 5A in Transgenic Mice

Kanda

Steele²,

Ray

2009

J Virol

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Hepatitis C virus (HCV) utilizes strategies to suppress or evade the host immune response for establishment of persistent infection. We have shown previously that HCV nonstructural protein 5A (NS5A) impairs tumor necrosis factor alpha (TNF-␣)-mediated apoptosis. In this study, we have examined the immunomodulatory role of HCV NS5A protein in transgenic mouse (NS5A-Tg) liver when mice were challenged with an unrelated hepatotropic adenovirus as a nonspecific stimulus. Hepatotropic adenovirus was introduced intravenously into NS5A-Tg mice and control mice, and virus clearance from liver was compared over a time course of 3 weeks. The differential mRNA expression levels of 84 cytokine-related genes, signal pathway molecules, transcription factors, and cell surface molecules were determined using real-time reverse transcription-PCR array. NS5A-Tg mice failed to clear adenovirus from liver up to 3 weeks postinfection while control mice cleared virus within 1 to 2 weeks. Subsequent study revealed that gamma interferon (IFN-␥) expression is inhibited at both the mRNA and protein levels in NS5A-Tg mice, and an inverse expression of transcription factors Gata-3 and Tbx21 is observed. However, TNF-␣ mRNA and protein expression were elevated in both NS5A-Tg and control mice. Together, our results suggested that HCV NS5A acts as an immunomodulator by inhibiting IFN-␥ production and may play an important role toward establishment of chronic HCV infection.

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“…The CX3CL1-CX3CR1 axis is strongly associated with HCC (43). In addition to the immunopathology of HCC, the CX3CL1-CX3CR1 axis could be associated with liver damage and fibrosis (44)(45)(46).…”

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confidence: 99%

Differential Expression of CX3CL1 in Hepatitis B Virus-Replicating Hepatoma Cells Can Affect the Migration Activity of CX3CR1 ⁺ Immune Cells

Kondo

Kimura

Tanaka

et al. 2015

J Virol

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The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection

Cited by 69 publications

References 50 publications

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Inhibition of Intrahepatic Gamma Interferon Production by Hepatitis C Virus Nonstructural Protein 5A in Transgenic Mice

Differential Expression of CX3CL1 in Hepatitis B Virus-Replicating Hepatoma Cells Can Affect the Migration Activity of CX3CR1 ⁺ Immune Cells

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The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection

Cited by 69 publications

References 50 publications

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Inhibition of Intrahepatic Gamma Interferon Production by Hepatitis C Virus Nonstructural Protein 5A in Transgenic Mice

Differential Expression of CX3CL1 in Hepatitis B Virus-Replicating Hepatoma Cells Can Affect the Migration Activity of CX3CR1 + Immune Cells

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Differential Expression of CX3CL1 in Hepatitis B Virus-Replicating Hepatoma Cells Can Affect the Migration Activity of CX3CR1 ⁺ Immune Cells