HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

Cell Rep. 2016 Oct 18;17(4):1128-1140. doi: 10.1016/j.celrep.2016.09.076.


Infectious and sterile inflammatory diseases are correlated with increased levels of high mobility group box 1 (HMGB1) in tissues and serum. Extracellular HMGB1 is known to activate Toll-like receptors (TLRs) 2 and 4 and RAGE (receptor for advanced glycation endproducts) in inflammatory conditions. Here, we find that TLR5 is also an HMGB1 receptor that was previously overlooked due to lack of functional expression in the cell lines usually used for studying TLR signaling. HMGB1 binding to TLR5 initiates the activation of NF-κB signaling pathway in a MyD88-dependent manner, resulting in proinflammatory cytokine production and pain enhancement in vivo. Biophysical and in vitro results highlight an essential role for the C-terminal tail region of HMGB1 in facilitating interactions with TLR5. These results suggest that HMGB1-modulated TLR5 signaling is responsible for pain hypersensitivity.

Keywords: HMGB1; Toll-like receptors; cytokines; inflammation; pain.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cytokines / biosynthesis
  • HEK293 Cells
  • HMGB1 Protein / chemistry
  • HMGB1 Protein / metabolism*
  • Humans
  • Hyperalgesia / metabolism*
  • Hyperalgesia / pathology*
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Jurkat Cells
  • Male
  • Mice
  • NF-kappa B / metabolism
  • Nitric Oxide / biosynthesis
  • Protein Binding
  • RAW 264.7 Cells
  • Rats, Sprague-Dawley
  • Signal Transduction*
  • Toll-Like Receptor 5 / metabolism*


  • Cytokines
  • HMGB1 Protein
  • NF-kappa B
  • Toll-Like Receptor 5
  • Nitric Oxide