Viral Hepatitis and Iron Dysregulation: Molecular Pathways and the Role of Lactoferrin

Abstract

The liver is a frontline immune site specifically designed to check and detect potential pathogens from the bloodstream to maintain a general state of immune hyporesponsiveness. One of the main functions of the liver is the regulation of iron homeostasis. The liver detects changes in systemic iron requirements and can regulate its concentration. Pathological states lead to the dysregulation of iron homeostasis which, in turn, can promote infectious and inflammatory processes. In this context, hepatic viruses deviate hepatocytes' iron metabolism in order to better replicate. Indeed, some viruses are able to alter the expression of iron-related proteins or exploit host receptors to enter inside host cells. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein belonging to the innate immunity, is endowed with potent antiviral activity, mainly related to its ability to block viral entry into host cells by interacting with viral and/or cell surface receptors. Moreover, Lf can act as an iron scavenger by both direct iron-chelation or the modulation of the main iron-related proteins. In this review, the complex interplay between viral hepatitis, iron homeostasis, and inflammation as well as the role of Lf are outlined.

Keywords: ferroportin; hepatitis; hepcidin; iron; iron homeostasis; iron proteins; lactoferrin; lactoferrin receptors; liver; viral infections.

Figure 1

Iron uptake and excretion in hepatocytes. Tf-bound ferric iron uptake is mediated by TfR1, inducing endocytosis. Once in the acidic endosome, ferric iron is reduced by a ferric reductase and exported to the cytoplasm by DMT1. The ferrous iron is then utilized for cell metabolism or sequestered into Ftn. Acquisition of NTBI involves the reductase-mediated ZIP-4 import as ferrous iron. Moreover, heme-bound iron is imported by LRP1 or though hemoglobin internalization. Despite the numerous uptake mechanisms, iron is exported only through the Fpn/Cp system. Tf: transferrin; Holo-Tf: transferrin-bound iron; Fpn: ferroportin; Cp: ceruloplasmin; TfR1: transferrin receptor 1; NTBI: non-transferrin-bound iron; ZIP-14: ZRT/IRT-like protein-14; DMT-1: divalent metal transporter 1; Ftn: ferritin; LRP1: Low Density Lipoprotein receptor related protein. This figure has been drawn, with few modifications, according to the scheme proposed by Knutson et al. [50].

Figure 2

Iron uptake and excretion in inflamed hepatocytes. The liver is the major organ responsible for iron storage upon inflammatory stimuli. The iron homeostasis disorders start with the up-regulation of systemic IL-6, which stimulates the synthesis of hepcidin by the liver. Hepcidin binding to Fpn leads to the internalization and lysosomal-mediated degradation of the permease, thus blocking iron export. Accordingly, Tf-independent and -dependent iron uptake systems are up-regulated (purple arrows), guaranteeing that excess systemic iron is accumulated in Ftn. Notably, intracellular iron overload induces ROS which, in turn, damage proteins, lipid membranes, and DNA, thus inducing tissue injury and organ failure. According to intracellular iron overload, anemia of inflammation is established.IL-6: interleukin-6; Fpn: ferroportin; Tf: transferrin; Holo-Tf: saturated transferrin; Apo-Tf: unsaturated transferrin; TfR1: transferring receptor 1; Ftn: ferritin; NTBI: non-transferrin-bound iron; ZIP-14: ZRT/IRT-like protein-14; DMT-1: divalent metal transporter 1; Ftn: ferritin; ROS: reactive oxygen species; LRP1: Low Density Lipoprotein receptor related protein.

Figure 3

Morphological evaluation and immunohistochemistry of lactoferrin and hepcidin in normal and HCV-infected liver performed according to the procedures reported in our previous papers [124,176,177]. (A) Hematoxylin and eosin stain (HE): morphology of a normal liver, with a regular histological appearance and a liver with chronic hepatitis C infection (HCV), with portal and periportal fibrosis and inflammation (blue arrows) together with steatosis (yellow arrows). (B) Immunohistochemistry: HCV infection induces a significant up-regulation of lactoferrin synthesis (red arrows), probably related to the activation of the inflammatory process. (C) Immunohistochemistry: HCV infection significantly down-regulates the expression of hepcidin compared to normal liver (green arrows). OM 20×. Scale bar = 50 μm.