Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection

Abstract

BackgroundHepatitis C Virus (HCV), a single stranded RNA virus, affects millions of people worldwide and leads to chronic infection characterized by chronic inflammation in the liver and in peripheral immune cells. Chronic liver inflammation leads to progressive liver damage. MicroRNAs (miRNA) regulate inflammation (miR-155, -146a and -125b) as well as hepatocyte function (miR-122).MethodsHere we hypothesized that microRNAs are dysregulated in chronic HCV infection. We examined miRNAs in the circulation and in peripheral monocytes of patients with chronic HCV infection to evaluate if specific miRNA expression correlated with HCV infection.ResultsWe found that monocytes from chronic HCV infected treatment-naïve (cHCV) but not treatment responder patients showed increased expression of miR-155, a positive regulator of TNFα, and had increased TNFα production compared to monocytes of normal controls. After LPS stimulation, miR-155 levels were higher in monocytes from cHCV patients compared to controls. MiR-125b, which has negative regulatory effects on inflammation, was decreased in cHCV monocytes compared to controls. Stimulation of normal monocytes with TLR4 and TLR8 ligands or HCV core, NS3 and NS5 recombinant proteins induced a robust increase in both miR-155 expression and TNFα production identifying potential mechanisms for in vivo induction of miR-155. Furthermore, we found increased serum miR-155 levels in HCV patients compared to controls. Serum miR-125b and miR-146a levels were also increased in HCV patients. Serum levels of miR-122 were elevated in cHCV patients and correlated with increased ALT and AST levels and serum miR-155 levels.ConclusionIn conclusion, our novel data demonstrate that miR-155, a positive regulator of inflammation, is upregulated both in monocytes and in the serum of patients with chronic HCV infection. Our study suggests that HCV core, NS3, and NS5 proteins or TLR4 and TLR8 ligands can mediate increased miR-155 and TNFα production in chronic HCV infection. The positive correlation between serum miR-155 and miR-122 increase in cHCV may be an indicator of inflammation-induced hepatocyte damage.

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

“…In rat models of liver fibrosis, cytokines were shown to increase the expression of both miR-146a and miR-21, which in turn sustain repression of hepatocyte nuclear factor 1a (HNF1a) in hepatocytes, thus enhancing hepatocellular inflammation, cytokine release, activation of HSC, and disease progression (55). This is also in line with previous studies showing an upregulation of miR-146a in the plasmas of mice subjected to liver inflammation induced by the cytidine-phosphate-guanosine (CpG) motif and lipopolysaccharide (LPS) (53). Interestingly, the same study highlighted enhanced miR-146a expression in mice with acetaminophen-induced liver injury characterized by little inflamma- .…”

“…1), we provided the first evidence that HCV induces upregulation of miR-146a-5p in hepatocytes. Interestingly, miR-146a has previously been associated with HCV infection: an increased expression of this miRNA was observed in the sera and PBMC of HCV-infected patients, suggesting a role for circulating miR-146-5p as a biomarker for hepatic injury (53,54). In line with this, hepatitis B virus (HBV) has also been shown to increase miR-146a in human hepatoma cell lines and chronically HBV-infected patient-derived liver tissues (69).…”

“…1D) (P ϭ 0.002, 0.005, and 0.03, respectively; two-tailed Mann-Whitney test), confirming that the HCV-mediated enhancement of miR-21-5p, miR-146a-5p, and miR-143-3p occurs in human hepatocytes. Interestingly, miR-146a-5p, which is a well-known immunoregulatory miRNA (52), was described to be upregulated in the sera and peripheral blood mononuclear cells (PBMC) of HCVinfected patients (53,54). Moreover, a recent piece of evidence points to an involvement of miR-146a in liver fibrosis in mice and humans, independently of HCV (55).…”

Plasma microRNA-586 is a new biomarker for acute graft-versus-host disease

“…However, in this study, we still have not found the correlation between miR-586 and some infection-related factors such as CRP or ESR yet. Previous studies indicate that miR-155 can be induced by the cytokines IFN-γ and IFN-β through TNF-α autocrine or paracrine signaling [40], and miR-155 is elevated in the serum of aGVHD patients [41] and during HCV infection [42]. Increased plasma miR-586 levels may also be caused by the Bcytokine storms^which occur in a number of infections.…”

Predictive prognostic role of miR-181a with discrepancy in the liver and serum of genotype 4 hepatitis C virus patients

“…Similarly, pre-treatment levels of miR-122 were reported to be higher in liver tissues of responders compared to NR GT1, 2, 3 and 4 HCV-infected patients (25). Furthermore, GT1, 2 and 3 SVR patients showed high pre-treatment levels of miR-155 in liver tissues and PBMCs, which decreased following viral clearance (26,27).…”