Published online Dec 21, 2020. doi: 10.3748/wjg.v26.i47.7513
Peer-review started: August 27, 2020
First decision: October 17, 2020
Revised: November 8, 2020
Accepted: December 6, 2020
Article in press: December 6, 2020
Published online: December 21, 2020
Currently, the molecular mechanisms of liver fibrosis are not fully understood. Recurrent liver injury or inflammation initiates wound healing along with fibrogenesis. However, what initiates this process is not clear. When cells die, damage-associated molecular patterns (DAMPs) are released. Histones are the most abundant DAMPs and are also ligands for TLR4, which in turn has been demonstrated to be involved in bile-duct-ligation-induced liver fibrosis. Lipopolysaccharide (LPS) is proposed to be a ligand for TLR4. Since recurrent liver injury does not naturally produce LPS but abundant extracellular histones, this study sought to investigate the potential roles of extracellular histones as TLR4 ligands in liver fibrosis.
Since our laboratory has been involved in studying the roles of DAMPs in critical illnesses, extracellular histones in liver fibrosis are of interest in terms of biological and clinical significance.
Our study aimed to clarify the roles of extracellular histones in fibrogenesis in vitro and in vivo.
In our study, a hepatic stellate (HSC) cell line and animal models of liver fibrosis were used. Intervention studies with non-anticoagulant heparin (NAHP) to detoxify histones and TLR4-blocking antibodies to inhibit TLR4 were performed. In addition, TLR4 and MyD88 knockout mice were used to support the theory that the TLR4-MyD88 signaling pathway is involved in liver fibrosis in the CCl4 mouse model.
High levels of circulating histones were present when fibrosis was induced by CCl4 in the mouse model. Extracellular histones stimulated HSC cells in vitro to increase production of collagen I and alpha-smooth muscle actin. NAHP inhibited histone-enhanced collagen production in vitro, and reduce liver injury and fibrosis in vivo. TLR4 was involved in histone-enhanced collagen I production by HSC cells. In vivo, the TLR4-MyD88 signaling pathway mediated liver fibrosis, but whether circulating histones were the major activators of the pathway was not clear.
Recurrent liver injury releases extracellular histones that potentially activate TLR4-MyD88 signaling to promote liver fibrosis. The ability of NAHP to detoxify circulating histones has the potential for treatment of liver injury and prevention of liver fibrosis.
Future studies demonstrating the contribution of circulating histones to activation of the TLR4-MyD88 signaling and downstream pathways will validate their role in liver fibrosis. Development of effective anti-histone therapies to reduce liver injury and prevent liver fibrosis have potential in the management of diseases with recurrent liver injury.