Targeting TLR4-dependent inflammation in post-hemorrhagic brain injury

Expert Opin Ther Targets. 2020 Jun;24(6):525-533. doi: 10.1080/14728222.2020.1752182. Epub 2020 Apr 17.


Recent data have implicated inflammation of the cerebrospinal fluid spaces after subarachnoid, intraventricular, and intracerebral hemorrhage to be a critical driver of multiple secondary brain injuries such as hydrocephalus, cerebral edema, and vasospasm. While TLR4-dependent reparative inflammation is an important protective response that can eliminate physical irritants and damaged cells, sustained or inappropriately triggered inflammation can initiate or propagate disease.Areas covered: We review recent advances in our understanding of how TLR4, including its upstream damage-associated molecular patterns and its downstream MyD88-dependent and independent signaling pathways, contributes to hemorrhage-induced inflammation in numerous brain diseases. We discuss prospects for the pharmacotherapeutic targeting of TLR4 in these disorders, including the use of repurposed FDA-approved agents.Expert opinion: TLR4 inhibitors with good blood-brain-barrier (BBB) penetration could be useful adjuncts in post-hemorrhagic hydrocephalus and multiple other diseases associated with brain hemorrhage and inflammation.

Keywords: CSF hypersecretion; Intracerebral hemorrhage; choroid plexus epithelium; intraventricular hemorrhage; neuroinflammation; subarachnoid hemorrhage; toll-like receptor 4.

Publication types

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

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain Edema / drug therapy
  • Brain Edema / etiology
  • Brain Edema / physiopathology
  • Brain Injuries / drug therapy*
  • Brain Injuries / etiology
  • Brain Injuries / physiopathology
  • Cerebral Hemorrhage / complications*
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / etiology
  • Inflammation / pathology
  • Molecular Targeted Therapy
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism


  • TLR4 protein, human
  • Toll-Like Receptor 4