Date Published: June 27, 2013
Publisher: Public Library of Science
Author(s): Qinghong Wang, Jijun Zhou, Bei Zhang, Zhiqiang Tian, Jun Tang, Yanhua Zheng, Zemin Huang, Yi Tian, Zhengcai Jia, Yan Tang, Jennifer C. van Velkinburgh, Qing Mao, Xiuwu Bian, Yifang Ping, Bing Ni, Yuzhang Wu, Aleem Siddiqui.
IL-23 regulates myriad processes in the innate and adaptive immune systems, and is a critical mediator of the proinflammatory effects exerted by Th17 cells in many diseases. In this study, we investigated whether and how hepatitis B virus (HBV) causes liver damage directly through the IL-23 signaling pathway. In biopsied liver tissues from HBV-infected patients, expression of both IL-23 and IL-23R was remarkably elevated. In vivo observations also indicated that the main sources of IL-23 were myeloid dendritic cells (mDCs) and macrophages. Analysis of in vitro differentiated immature DCs and macrophages isolated from healthy donors revealed that the HBV surface antigen (HBsAg) efficiently induces IL-23 secretion in a mannose receptor (MR)-dependent manner. Culture with an endosomal acidification inhibitor and the dynamin inhibitor showed that, upon binding to the MR, the HBsAg is taken up by mDCs and macrophages through an endocytosis mechanism. In contrast, although the HBV core antigen (HBcAg) can also stimulate IL-23 secretion from mDCs, the process was MR- and endocytosis-independent. In addition, IL-23 was shown to be indispensible for HBsAg-stimulated differentiation of naïve CD4+ T cells into Th17 cells, which were determined to be the primary source of IL-17 in HBV-infected livers. The cognate receptor, IL-17R, was found to exist on the hepatic stellate cells and mDCs, both of which might represent the potential target cells of IL-17 in hepatitis B disease. These data provide novel insights into a yet unrecognized mechanism of HBV-induced hepatitis, by which increases in IL-23 expression, through an MR/endocytosis-dependent or -independent manner, produce liver damage through the IL-23/IL-17 axis.
Hepatitis B virus (HBV) is a noncytopathic, hepatotropic and stealth DNA virus that has been implicated in the etiology of chronic hepatitis B (CHB) and HBV-associated acute-on-chronic liver failure (ACLF). HBV-induced hepatic injury is known to be mediated by a variety of immunocytes that play important roles in the development and progression of hepatitis B. Among these host immune cells, the T cells are considered the main effector cells contributing to the pathogenesis of hepatitis B disease. Furthermore, the CD4+ and CD8+ T cell subpopulations have both been shown to play key roles in antiviral defenses, as well as in the hepatocellular damage that accompanies hepatitis B viral infection .
Proper inflammatory response is crucial to the positive outcome of patients infected by hepatitis B virus , . The host IL-23 signaling pathway is critical to the immune response and is the target of manipulation by pathogens seeking to establish infection , . Here, we describe our investigations into the role of intrahepatic IL-23/IL-23R signaling during development of lethal or chronic hepatitis. We found that the IL-23/IL-23R pathway was strongly activated in liver tissues from HBV infected human patients, as compared with those from healthy controls. Moreover, we determined that in these patients IL-23 was principally derived from the intrahepatic myeloid DC population and macrophages. When stimulated by HBsAg and HBcAg in vitro, monocyte-derived DCs and macrophages produced large amounts of IL-23. The effect for HBsAg was dependent on the availability and function of the surface MR, while the mechanisms underlying the HBcAg-induced effect remain unclear. After binding to MRs, HBsAg entered the cells via endocytosis, which subsequently induced the polarization of Th17 cells from naïve CD4+ T cells and IL-17 production. In addition, IL-17R expression was mainly detected on HSCs and a few mDCs in liver tissue, suggesting that these cells may be potential targets of IL-17 in hepatitis B patients.