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Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

Cellular & Molecular Immunology volume 12, pages 729–742 (2015)Cite this article

Abstract

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.

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Acknowledgements

This work was financially supported by the National S&T Major Project on Major Infectious Diseases (Grant 2012ZX10001-008 and 2008ZX10001-010), the National Basic Research Program of China (973 Program) (Grant 2012CB518904) from the Ministry of Science and Technology of the People's Republic of China, and the National Natural Science Foundation of China (Grant 81202381). We sincerely thank Dr George Dacai Liu for his critical comments and revision of the article. We are thankful to the Core Facility and Technical Support, Wuhan Institute of Virology and Xuefang An for valuable assistance in the animal studies, as well as Ying Sun, Rong Bao and Benxia He for their help with the sample collection.

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  1. Dr HM Yan, Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China. E-mail: hmyan@wh.iov.cn

Authors and Affiliations

  1. Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China

    Yang Xiao, Fang Liu, Jingyi Yang, Maohua Zhong, Ejuan Zhang, Yaoming Li, Dihan Zhou, Yuan Cao, Wei Li, Jie Yu, Yi Yang & Huimin Yan

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Xiao, Y., Liu, F., Yang, J. et al. Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice. Cell Mol Immunol 12, 729–742 (2015). https://doi.org/10.1038/cmi.2014.110

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