The macrophage activation marker <scp>CD</scp>163 is associated with <scp>IL</scp>28B genotype and hepatic inflammation in chronic hepatitis C virus infected patients

Dultz, G.; Gerber, Ludmila; Zeuzem, Stefan; Sarrazin, Christoph; Waidmann, Oliver

doi:10.1111/jvh.12488

Cited by 22 publications

(18 citation statements)

References 28 publications

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“…Unlike IFN-λ4 which is weakly secreted by hepatocytes (53, 54), IFN-λs 1–3 are highly expressed, and can exert paracrine effects on surrounding immune cells. This is consistent with reports showing increased Mϕ activation in patients possessing the favorable IFNL genotype (55). The importance of the Mϕ response is additionally underscored by the fact that Mϕ but not hepatocyte ISG expression is positively associated with both the favorable IFNL genotype that produces increased IFN-λ3 and antiviral response (56, 57).…”

Section: Discussionsupporting

confidence: 93%

Macrophage Coordination of the Interferon Lambda Immune Response

et al. 2019

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Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ. While CD14+ monocytes do not express the IFN-λ receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-λ stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-λ induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-λ ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-λ dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-λ unresponsive lymphocytes.

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Section: Discussionsupporting

confidence: 93%

Macrophage Coordination of the Interferon Lambda Immune Response

et al. 2019

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“…The observations of rapidly improved ALT and sCD163 values combined with a decrease in liver stiffness within the period of DAA therapy suggest prompt resolution of liver inflammation in parallel with clearance of the hepatitis C virus. This is supported by several studies with similar results regarding inflammatory mediators, sCD163 and liver stiffness during DAA therapy …”

Section: Discussionsupporting

confidence: 84%

“…This is supported by several studies with similar results regarding inflammatory mediators, sCD163 and liver stiffness during DAA therapy. [34][35][36] Next, we examined the long-term effects of DAA therapy on liver fibrosis during one-year follow-up after treatment and found a continued decrease in liver stiffness. Whereas ALT and sCD163 levels had plateaued already at EOT, liver stiffness continued to health.…”

Section: Discussionmentioning

confidence: 99%

Time‐dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct‐acting antiviral therapy of chronic hepatitis C

Laursen

Siggaard

Kazankov

et al. 2019

Journal of Viral Hepatitis

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Sofosbuvir‐based direct‐acting antiviral (DAA) therapy generally cures chronic hepatitis C (CHC) infections, however, the effects on the underlying liver disease and the potential rate of recovery are unclear. We aimed to investigate the effects of DAA therapy on liver inflammation, fibrosis, metabolic function and cognitive function and the time course in CHC patients with advanced liver disease. Seventy‐one CHC patients with advanced liver disease were studied before, during and one year after successful sofosbuvir‐based DAA therapy. Liver inflammation was assessed by plasma sCD163 and sMR levels (ELISA), fibrosis by liver stiffness (transient elastography), function by galactose elimination capacity (GEC) and cognitive performance by continuous reaction time (CRT). During DAA therapy, we observed a rapid sCD163 decline from baseline to end of treatment (6.9 vs 3.8 mg/L, P < .0001), whereas the change in sMR was more subtle (0.37 vs 0.30 mg/L, P < .0001). Liver stiffness decreased by 20% at end of treatment (17.8 vs 14.3 kPa, P < .0001), together suggesting rapid resolution of liver inflammation. One year after treatment, liver stiffness decreased by an additional 15% (P < .0001), suggestive of fibrosis regression. The GEC improved at follow‐up (all: 1.74 vs 1.98 mmol/min), mainly at 12 weeks post‐treatment, both in patients with cirrhosis (n = 56) and those with advanced liver fibrosis (n = 15) (P < .001). The CRT improved at one‐year follow‐up (1.86 vs 2.09, P = .04). In conclusion, successful DAA therapy of CHC proves beneficial in advanced liver disease, with an initial rapid resolution of liver inflammation and a subsequent gradual but steady improvement in liver fibrosis, metabolic liver function and reaction time.

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“…sCD163 is an important marker of macrophage activation, involved in the activation of hepatic stellate cells during the progression of chronic liver disease [27,28]. In our study, we found higher levels of sCD163 in HCV-infected patients compared to HD, confirming that sCD163 plays an important role in the pathogenesis of HCV infection [29]. In accordance with Kazankow K. et al [16], we found higher levels of sCD163 in patients with advanced fibrosis (F4) compared to patients with mild fibrosis (F0-F2), showing that sCD163 could play a role in determining the severity of hepatitis.…”

Section: Discussionsupporting

confidence: 76%

Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon

Mascia¹,

Vita²,

Zuccalà³

et al. 2017

PLoS ONE

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Background and aimsIncreased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10 (CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported in HCV infection. The aim of this study was to compare, sCD163 and sCD14 levels in HCV-infected patients undergoing direct acting antiviral (DAA)-containing regimens with or without interferon (IFN).MethodssCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma samples from 25 HCV-infected patients undergoing IFN-based treatment plus telaprevir or boceprevir and 28 HCV infected subjects treated with DAA IFN-free regimens. Twenty-five healthy donors (HD) were included as controls.ResultsAt baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected patients than in HD. CXCL10 and sCD163 levels were significantly decreased in responder (R) patients who achieved sustained virological response (SVR), with both IFN-based and IFN-free regimens, while they were persistently elevated in non-responders (NR) patients who stopped IFN-based treatments because of failure or adverse events. Conversely, sCD14 levels were apparently unchanged during therapy, but at the end of treatment the levels reached normal ranges. Comparing the two regimens, the extent of CXCL10 reduction was more pronounced in patients undergoing DAA IFN-free therapies, whereas sCD163 and sCD14 reduction was similar in the two groups.Interestingly, only in IFN-based regimens baseline sCD163 levels were significantly higher in NR than in R patients, while in the IFN-free treatment group also patients with high sCD163 plasma levels obtained SVR. At the end of therapy, even if the biomarkers were largely decreased, their levels remained significantly higher compared to HD. Only in the early fibrosis stages, sCD163 values tended to normalize.ConclusionsThese results indicate that IFN-free regimens including newer DAA induce an early and marked decrease in circulating inflammatory biomarkers. However, the full normalization of biomarkers was not obtained, especially in patients with advanced fibrosis, thus underlying the need for a treatment in the early stages of HCV infection.

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The macrophage activation marker CD163 is associated with IL28B genotype and hepatic inflammation in chronic hepatitis C virus infected patients

Cited by 22 publications

References 28 publications

Macrophage Coordination of the Interferon Lambda Immune Response

Macrophage Coordination of the Interferon Lambda Immune Response

Time‐dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct‐acting antiviral therapy of chronic hepatitis C

Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon

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