Research Papers:

Knockout of toll-like receptor impairs nerve regeneration after a crush injury

Ching-Hua Hsieh _, Cheng-Shyuan Rau, Pao-Jen Kuo, Shu-Hsuan Liu, Chia-Jung Wu, Tsu-Hsiang Lu, Yi-Chan Wu and Chia-Wei Lin

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Oncotarget. 2017; 8:80741-80756. https://doi.org/10.18632/oncotarget.20206

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Ching-Hua Hsieh1,2,*, Cheng-Shyuan Rau3,*, Pao-Jen Kuo1, Shu-Hsuan Liu4, Chia-Jung Wu1, Tsu-Hsiang Lu1, Yi-Chan Wu1 and Chia-Wei Lin1

1Department of Plastic and Reconstructive Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

2Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Kaohsiung, Taiwan

3Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

4Faculty of Health Sciences, McMaster University, Hamilton, Canada

*These authors have contributed equally to this work

Correspondence to:

Ching-Hua Hsieh, email: [email protected]

Keywords: myelination, peripheral nerve regeneration, Schwann cells, sciatic nerve crush injury, toll-like receptors

Received: May 09, 2017    Accepted: July 12, 2017    Published: August 10, 2017


Background: Toll-like receptors (TLRs) are involved in the initiation of Schwann cell activation and subsequent recruitment of macrophages for clearance of degenerated myelin and neuronal debris after nerve injury. The present study was designed to investigate the regenerative outcome and expression of myelination-related factors in Tlr-knockout mice following a sciatic nerve crush injury.

Materials and methods: A standard sciatic nerve crush injury, induced by applying constant pressure to the nerve with a No. 5 jeweler’s forceps for 30 s, was performed in C57BL/6, Tlr2-/-, Tlr3-/- , Tlr4-/-, Tlr5-/-, and Tlr7-/- mice. Quantitative histomorphometric analysis of toluidine blue-stained nerve specimens and walking track analysis were performed to evaluate nerve regeneration outcomes. PCR Arrays were used to detect the expression of neurogenesis-related genes of dorsal root ganglia as well as of myelination-related genes of the distal nerve segments.

Results: Worse nerve regeneration after nerve crush injury was found in all Tlr-knockout mice than in C57BL/6 mice. Delayed expression of myelin genes and a different expression pattern of myelination-related neurotrophin genes and transcription factors were found in Tlr-knockout mice in comparison to C57BL/6 mice. In these TLR-mediated pathways, insulin-like growth factor 2 and brain-derived neurotrophic factor, as well as early growth response 2 and N-myc downstream-regulated gene 1, were significantly decreased in the early and late stages, respectively, of nerve regeneration after a crush injury.

Conclusions: Knockout of Tlr genes decreases the expression of myelination-related factors and impairs nerve regeneration after a sciatic nerve crush injury.

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PII: 20206