Role of Toll like receptor 4 signaling pathway in the secondary damage induced by experimental spinal cord injury

Daniela Impellizzeri, Akbar Ahmad, Rosanna Di Paola, Michela Campolo, Michele Navarra, Emanuela Esposito, Salvatore Cuzzocrea

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Toll-like receptors (TLRs) are signaling receptors in the innate immune system that is specific immunologic response to systemic bacterial infection and injury. TLRs contribute to the initial induction of neuroinflammation in the CNS. In spinal cord injury (SCI) intricate immune cell interactions are triggered, typically consisting of a staggered multiphasic immune cell response, which can become deregulated. The present study aims to evaluate the role of TLR4 signaling pathway in the development of secondary damage in a mouse model of SCI using TLR4-deficient (TLR4-KO) mice such as C57BL/10ScNJ and C3H/HeJ mice. We evaluated behavioral changes, histological, immunohistochemistry and molecular assessment in TLR4-KO after SCI. SCI was performed on TLR4-KO and wild-type (WT) mice by the application of vascular clips (force of 24. g) to the dura via a four-level T5-T8 laminectomy. Mice were sacrificed at 24. h after SCI to evaluate the various parameters. SCI TLR4 KO mice developed severer hind limb motor dysfunction and neuronal death by histological evaluation, myeloid differentiation primary response 88 (Myd88) expression as well as an increase in nuclear factor NF-κB activity, tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels, glial fibrillary acidic protein (GFAP), microglia marker (CD11β), inducible nitric oxide synthases (iNOS), poly-ADP-ribose polymerase (PARP) and nitrotyrosine expression compared to WT mice. Moreover, the absence of TLR4 also caused a decrease in phosphorylated interferon regulatory transcription factor (p-IRF3) and interferon (IFN-β) release. In addition, SCI TLR4 KO mice showed in spinal cord tissues a more pronounced up-regulation of Bax and a down-regulation of Bcl-2 compared to SCI WT mice. Finally, we clearly demonstrated that TLR4 is important for coordinating post-injury sequel and in regulating inflammation after SCI.

Original languageEnglish (US)
Pages (from-to)1039-1049
Number of pages11
Issue number9
StatePublished - Sep 1 2015
Externally publishedYes


  • Apoptosis
  • MyD88
  • Nuclear factor-κB
  • Spinal cord injury
  • Toll-like receptor-4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Hematology


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