Glycyrrhetinic acid alleviates hepatic inflammation injury in viral hepatitis disease via a HMGB1-TLR4 signaling pathway

Abstract

Various human disorders are cured by the use of licorice, a key ingredient of herbal remedies. Glycyrrhizic acid (GL), a triterpenoid glycoside, is the aqueous extract from licorice root. Glycyrrhetinic acid (GA) has been reported to be a major bioactive hydrolysis product of GL and has been regarded as an anti-inflammatory agent for the treatment of a variety of inflammatory diseases, including hepatitis. However, the mechanism by which GA inhibits viral hepatic inflammatory injury is not completely understood. In this study, we found that, by consecutively treating mice with a traditional herbal recipe, licorice plays an important role in the detoxification of mice. We also employed a murine hepatitis virus (MHV) infection model to illustrate that GA treatment inhibited activation of hepatic inflammatory responses by blocking high-mobility group box 1 (HMGB1) cytokine activity. Furthermore, decreased HMGB1 levels and downstream signaling triggered by injection of a neutralizing HMGB1 antibody or TLR4 gene deficiency, also significantly protected against MHV-induced severe hepatic injury. Thus, our findings characterize GA as a hepatoprotective therapy agent in hepatic infectious disease not only by suppressing HMGB1 release and blocking HMGB1 cytokine activity, but also via an underlying viral-induced HMGB1-TLR4 immunological regulation axis that occurs during the cytokine storm. The present study provides a new therapy strategy for the treatment of acute viral hepatitis in the clinical setting.

HMGB1 in inflammation and cancer

“…Pyroptotic macrophage death may accelerate undesirable immune hyperactivity and immunosuppression, which is a potential mechanism associated with late mortality from sepsis [8]. In hepatic infectious disease, the release and activity of HMGB1 as a cytokine could be suppressed by glycyrrhizinic acid (GA) [9]. By binding with TLR4, HMGB1 regulates the hepatitis viruses-induced immunological axis, providing a new therapy strategy for the treatment of acute viral hepatitis in the clinical practice [10].…”

Exploring the Pivotal Immunomodulatory and Anti-Inflammatory Potentials of Glycyrrhizic and Glycyrrhetinic Acids

“…TLRs are capable of modulating several immune responses, especially during the infectious process [ 128 ]. Several studies have shown that the secretion of TLR-3, TLR-4, TLR-7, TLR-9, and TLR-10 genes from hepatic tissue was upregulated in some viral infection models [ 129 , 130 ], and GA or GL is capable of inhibiting these receptors ( Table 1 ) [ 131 – 134 ]. It was established that the TLR-4 pathway comprises of two dissimilar signaling pathways such as the myeloid differentiating primary response gene 88- (MyD88-) dependent as well as the MyD88-independent pathway [ 135 , 136 ].…”

“…A study revealed that TLR-4 was the fundamental receptor of the innate immune signaling responses to influenza virus as well as other respiratory viruses [ 137 ]. Several studies have shown that the TLR-4 was more associated with respiratory syncytial virus and human papillomavirus infections [ 129 , 138 , 139 ]. Shi et al revealed that TLR-4 gene deficiency was not associated with the downregulation of virus titer in the liver during MHV-A59 infection [ 129 ].…”

“…Several studies have shown that the TLR-4 was more associated with respiratory syncytial virus and human papillomavirus infections [ 129 , 138 , 139 ]. Shi et al revealed that TLR-4 gene deficiency was not associated with the downregulation of virus titer in the liver during MHV-A59 infection [ 129 ]. They observed that in MHV-A59 infection, the HMGB1-TLR-4 axis utilizes proinflammatory activities without directly influencing virus replication [ 129 ].…”

“…Shi et al revealed that TLR-4 gene deficiency was not associated with the downregulation of virus titer in the liver during MHV-A59 infection [ 129 ]. They observed that in MHV-A59 infection, the HMGB1-TLR-4 axis utilizes proinflammatory activities without directly influencing virus replication [ 129 ].…”