Toll-like receptor 5 signaling restrains T-cell/natural killer T-cell activation and protects against concanavalin A-induced hepatic injury

Hepatology. 2017 Jun;65(6):2059-2073. doi: 10.1002/hep.29140. Epub 2017 May 4.


Toll-like receptor-5 (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 concanavalin A (Con A)-mediated liver injury. Here, we show that TLR5 is highly up-regulated in the hepatic mononuclear cells of mice during Con A-induced hepatitis. Increased mortality and liver histopathology of TLR5-deficient mice correlated with excessive production of proinflammatory cytokines, suggesting that TLR5 knockout mice were more susceptible to Con A-induced hepatitis. We also report 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 proinflammatory 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-cell/natural killer T-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, interleukin-6 elevation induced by CBLB502 is an important protective factor against Con A-induced liver injury. In addition, we demonstrate that CBLB502 suppresses α-galactosylceramide-induced natural killer T cell-dependent inflammatory liver injury.

Conclusion: 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. (Hepatology 2017;65:2059-2073).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy, Needle
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / blood
  • Chemical and Drug Induced Liver Injury / mortality
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Concanavalin A / pharmacology
  • Concanavalin A / toxicity*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Flow Cytometry
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Immunohistochemistry
  • Inflammation Mediators / blood
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / immunology*
  • Peptides / pharmacology*
  • Random Allocation
  • Reference Values
  • Signal Transduction
  • Survival Rate
  • Toll-Like Receptor 5 / drug effects
  • Toll-Like Receptor 5 / metabolism*


  • CBLB502
  • Cytokines
  • Inflammation Mediators
  • Peptides
  • Toll-Like Receptor 5
  • Concanavalin A