Evidence for a detrimental role of TLR8 in ischemic stroke

Exp Neurol. 2013 Dec;250:341-7. doi: 10.1016/j.expneurol.2013.10.012. Epub 2013 Oct 24.

Abstract

Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors that initiate signals in response to diverse pathogen-associated molecular patterns. Several groups have recently reported a role for TLR2 and TLR4 in ischemic stroke-induced brain injury. However, relatively little is known about the role of TLR8 in ischemic stroke. Here we provide the first evidence that TLR8 activation plays a detrimental role in stroke outcome by promoting neuronal apoptosis and T cell-mediated post-stroke inflammation. TLR8 is expressed in cerebral cortical neurons, where its levels and downstream signaling via JNK are increased in response to oxygen glucose deprivation (OGD). Treatment with a TLR8 agonist activated pro-apoptotic JNK and increased neuronal cell death during OGD. Furthermore, selective knockdown of TLR8 using siRNA protected SH-SY5Y cells following OGD, and TLR8 agonist administration in vivo increased mortality, neurological deficit and T cell infiltration following stroke. Taken together, our findings indicate a detrimental role for neuronal TLR8 signaling in the triggering of post-stroke inflammation and neuronal death.

Keywords: Apoptosis; Brain injury; Ischemic stroke; R848; TLR8.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Line
  • Disease Models, Animal
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Inflammation / immunology
  • Inflammation / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Stroke / immunology
  • Stroke / metabolism*
  • Toll-Like Receptor 8 / immunology
  • Toll-Like Receptor 8 / metabolism*

Substances

  • TLR8 protein, mouse
  • Toll-Like Receptor 8