TLR5 signaling restrains T/NKT cell activation and protects against concanavalin A-induced hepatic injury.

Wang L, Zhang W, Ge CH et al.

Department of pharmaceutical engineering, Tianjin University, Tianjin, China, 300072.

Hepatology (Baltimore, Md.). Mar 2017.

TLR5 signaling regulates the immune privileged status of the liver and is involved in hepatic immune disorders. However, the role of TLR5 has not yet been investigated in experimental models of Con A-mediated liver injury. Here, we show that TLR5 is highly upregulated in the hepatic mononuclear cells (MNCs) of mice during Con A-induced hepatitis. Increased mortality and liver histopathology of TLR5-deficient mice correlated with excessive production of pro-inflammatory cytokines, suggesting that TLR5 knockout mice were more susceptible to Con A-induced hepatitis. We also reported for the first time that administration of CBLB502, an exogenous TLR5 agonist, substantially alleviated Con A-mediated hepatitis in wild-type mice as shown by increased survival rates, reduced aminotransferase and pro-inflammatory cytokine production, impaired lymphocyte infiltration and ameliorated hepatocyte necrosis and/or apoptosis. Mechanistic studies revealed that CBLB502 acts as a negative regulator in limiting T/NKT cell activity and cytokine production in the Con A-hepatitis model. Bone marrow transplantation experiments showed that TLR5 in bone marrow-derived cells contributed to the hepatoprotective efficacy of CBLB502 against Con A-induced liver injury. Moreover, IL-6 elevation induced by CBLB502 is an important protective factor against Con A-induced liver injury. In addition, we demonstrated that CBLB502 suppresses α-Galcer-induced NKT cell-dependent inflammatory liver injury.The TLR5 signaling pathway plays an important role in T cell-mediated hepatic injury and may be exploited for therapeutic treatment of inflammatory liver diseases. This article is protected by copyright. All rights reserved.