Profile of 5-HT2A receptor involved in signaling cascades associated to intracellular inflammation and apoptosis in hepatocytes and its role in carbon tetrachloride-induced hepatotoxicity

• Published in: Cellular signalling 2023-05, Vol.105, p.110612-110612, Article 110612
• Main Authors: Zhang, Yuxin, Wang, Yizhou, Zhang, Kun, Liang, Xiurui, Guan, Jing, Jin, Jiaqi, Zhang, Yi, Xu, Fan, Yang, Lin, Fu, Jihua
• Format: Article
• Language: English
• Subjects: 5-HT degradation; 5-HT2A receptor; Cell injury; Protein kinase C epsilon; Reactive oxygen species; Signaling cascade
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2023.110612

Previously, we found that the 5-HT2A receptor plays a key role in cell injury. However, the mechanism by which the 5-HT2A receptor mediates intracellular processes remains unclear. In this study, we aimed to clarify this intracellular process in hepatocyte LO2 cells and evaluate its role in CCl4-induced hepatotoxicity in mice. In vitro, both the agonist and overexpression of 5-HT2A receptor could promote 5-HT degradation by upregulating the expression of 5-HT synthases and monoamine oxidase-A (MAO-A) to cause overproduction of ROS in mitochondria. We refer to this as the activation of the 5-HT degradation system (5DS) axis, which leads to the phosphorylation of JNK, p38 MAPK, STAT3, and NF-κB; upregulation of Bax, cleaved-caspase3, and cleaved-caspase9; and downregulation of Bcl-2, followed by apoptosis and oversecretion of TNF-α and IL-1β in cells. This phenomenon could be markedly blocked by the 5-HT2A receptor antagonist, MAO-A inhibitor, or gene-silencing MAO-A. Through protein kinases C epsilon (PKCε) agonist treatment and gene silencing of the PKCε and 5-HT2A receptor, we demonstrated that the 5-HT2A receptor controls 5-HT synthases and MAO-A expression via the PKCε pathway in cells. Unexpectedly, we discovered that PKCε-mediated phosphorylation of the AKT/mTOR pathway is also a consequence of the activation of the 5DS axis. Furthermore, we confirmed that the inhibition of the 5DS axis using the 5-HT2A receptor antagonist could prevent hepatotoxicity induced by CCl4 both in vitro and in vivo, inhibiting the aforementioned signaling cascades, inflammation, and apoptosis, and that the 5DS activation area overlapped the necrotic area of mouse liver. Taken together, we revealed a 5DS axis in hepatocytes that controls the signaling cascades associated with inflammation and apoptosis and confirmed its role in CCl4-induced hepatotoxicity. •A 5-HT degradation system (5DS) axis is identified in hepatocytes.•In 5DS axis, 5-HT2A receptor mediates 5-HT synthases and MAO-A expression by PKCε at the gene level.•5DS axis controls ROS production in mitochondria and is activated in hepatocytes exposed to CCl4.•Phosphorylation of JNK, p38, STAT3, NF-κB and AKT etc. depends on 5DS axis activation.•CCl4 induces hepatocyte damage by activating 5DS axis, leading to liver injury.