Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury

J Immunol. 2011 Sep 1;187(5):2626-31. doi: 10.4049/jimmunol.1003930. Epub 2011 Jul 22.


We previously reported that extracellular histones are major mediators of death in sepsis. Infusion of extracellular histones leads to increased cytokine levels. Histones activate TLR2 and TLR4 in a process that is enhanced by binding to DNA. Activation of TLR4 is responsible for the histone-dependent increase in cytokine levels. To study the impact of histone release on pathology we used two models: a Con A-triggered activation of T cells to mimic sterile inflammation, and acetaminophen to model drug-induced tissue toxicity. Histones were released in both models and anti-histone Abs were protective. TLR2- or TLR4-null mice were also protected. These studies imply that histone release contributes to death in inflammatory injury and in chemical-induced cellular injury, both of which are mediated in part through the TLRs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Histones / metabolism*
  • Liver / injuries*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Systemic Inflammatory Response Syndrome / metabolism*
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / metabolism*


  • Histones
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4