High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4

Glia. 2014 Jan;62(1):26-38. doi: 10.1002/glia.22581. Epub 2013 Oct 28.


Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.

Keywords: DAMP; controlled cortical impact; innate immunity; intracranial pressure; neuroinflammation.

Publication types

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

MeSH terms

  • Acetates / pharmacology
  • Animals
  • Brain Edema / etiology*
  • Brain Edema / pathology
  • Brain Injuries / cerebrospinal fluid
  • Brain Injuries / complications*
  • Cells, Cultured
  • Cerebral Cortex / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • HMGB1 Protein / metabolism*
  • Humans
  • Immunologic Factors / pharmacology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Microglia / drug effects
  • Microglia / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oxazoles / pharmacology
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*


  • 3-phenyl-4,5-dihydro-5-isoxazole acetic acid
  • Acetates
  • Excitatory Amino Acid Antagonists
  • HMGB1 Protein
  • Immunologic Factors
  • Oxazoles
  • Ribosomal Proteins
  • Rsp3a1 protein, mouse
  • Toll-Like Receptor 4