Mannan binding lectin-associated serine protease 1 is induced by hepatitis C virus infection and activates human hepatic stellate cells

Abstract

SummaryMannan binding lectin (MBL)-associated serine protease type 1 (MASP-1) has a central role in the lectin pathway of complement activation and is required for the formation of C3 convertase. The activity of MASP-1 in the peripheral blood has been identified previously as a highly significant predictor of the severity of liver fibrosis in hepatitis C virus (HCV) infection, but not in liver disease of other aetiologies. In this study we tested the hypotheses that expression of MASP-1 may promote disease progression in HCV disease by direct activation of hepatic stellate cells (HSCs) and may additionally be up-regulated by HCV. In order to do so, we utilized a model for the maintenance of primary human HSC in the quiescent state by culture on basement membrane substrate prior to stimulation. In comparison to controls, recombinant MASP-1 stimulated quiescent human HSCs to differentiate to the activated state as assessed by both morphology and up-regulation of HSC activation markers α-smooth muscle actin and tissue inhibitor of metalloproteinase 1. Further, the expression of MASP-1 was up-regulated significantly by HCV infection in hepatocyte cell lines. These observations suggest a new role for MASP-1 and provide a possible mechanistic link between high levels of MASP-1 and the severity of disease in HCV infection. Taken together with previous clinical observations, our new findings suggest that the balance of MASP-1 activity may be proinflammatory and act to accelerate fibrosis progression in HCV liver disease.

Hepatitis C Virus RNA Functionally Sequesters miR-122

“…It is tantalizing to speculate that miR-122 sequestration in a chronic HCV infection may be a molecular link to the heterogeneous liver dysfunction that characterizes HCV induced disease. Indeed, a number of miR-122 targets that we confirm or establish via CLIP and reporter measurements, such as P4HA1, PKM2, and MASP1 are known to be upregulated in fibrosis or HCC (Jung et al, 2011; Li et al, 2013a), with MASP1 notable for being specifically linked with HCV-associated HCC (Saeed et al, 2013). Still, there are challenges for a direct demonstration of an HCV miR-122 sponge in vivo .…”

Serum MASP-1 in complex with MBL activates endothelial cells

“…After the pattern recognition molecules bind to the activator structures, the Recently it has been shown that MASP-1 also activates hepatic stellate cells (Saeed et al, 2013). Although the mechanism is not clarified yet, it seems likely that MASP-1 cleaves protease activated receptor on the hepatic cells.…”

MBL-associated serine proteases (MASPs) and infectious diseases

“…Very similar results were obtained by others in an Egyptian cohort, again presenting a strong association of HCV-induced liver fibrosis with the activity of the MBL/MASP-1 complex, adjusted for MBL levels (P = 0.003) (El Saadany et al, 2011). Furthermore, both MBL2 and MASP1 genes were up-regulated, presenting higher mRNA expression in hepatocyte cell lines infected with the genotype 2a JFH-1 HCV clone, as revealed by two different groups using microarray and real-time RT-PCR analysis (Blackham et al, 2010;Saeed et al, 2013). Activated recombinant MASP-1 was actually shown to directly cause hepatic stellate cells (HSC) to differentiate to a myofibroblast phenotype in vitro, as measured both by morphology and by the expression of alpha smooth muscle actin (␣-SMA) and tissue inhibitor of metalloproteinase-1 (TIMP-1) (Saeed et al, 2013).…”

“…Among patients with different cardio-and cerebrovascular diseases, MASP-1 levels were highest in patients with subacute myocardial infarction (median 12 g/mL) and lowest in those with acute ischemic stroke (median 8.6 g/mL) (Frauenknecht et al, 2013). In addition, the expression of MASP-1 was observed to be up-regulated in primary uterine leiomyosarcoma (Davidson et al, 2014) and in HCV infected-hepatocyte cell lines (Saeed et al, 2013). Having much higher propensity for autoactivation than MASP-2 (Ambrus et al, 2003), MASP-1 activates MASP-2 in heterocomplexes of large oligomeric MBL and produces 60% of C2a responsible for C3 convertase formation Héja et al, 2012b).…”