Flagellin is a potent activator of a broad range of cell types that are involved in innate and adaptive immunity. Therefore, it is a good adjuvant candidate for
vaccines, and it might function as a
biological protectant against both major
acute radiation syndrome during
cancer radiotherapy and a mitigator of radiation emergencies. However, accumulating evidence has implicated
flagellin in the occurrence of some inflammatory diseases, such as acute
lung inflammation, cardiovascular collapse and
inflammatory bowel disease. The aim of this study was to elucidate whether only flagellin-TLR5 signaling activation plays a role in the pathophysiology of liver or whether some other
flagellin activity also contributes to liver injury either via
bacterial infections or during clinical applications. Recombinant
flagellin proteins with or without TLR5-stimulating activity were used to evaluate the role of flagellin-TLR5 signaling in liver injury in wild-type and TLR5 KO mice. Gross lesions and large areas of hepatocellular
necrosis were observed in liver tissue 12 h after the intraperitoneal administration of 100 or 200 µg
flagellin (FliC) in a dose- and time-dependent manner in wild-type mice, but not in TLR5 KO mice. Deletion of the N-terminal or TLR5 binding domain of
flagellin inhibited
flagellin-induced inflammatory responses and the subsequent acute liver function abnormality and damage. These data confirmed that
flagellin is an essential determinant of liver injury and demonstrated that the over-activation of TLR5 signaling by high-dose
flagellin caused acute inflammatory responses, neutrophil accumulation and oxidative stress in the liver, which contributes to the progression and severity of
flagellin-induced liver injury.