HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

Nabanita Das, Varun Dewan, Peter M. Grace, Robin J. Gunn, Ryo Tamura, Netanel Tzarum, Linda R. Watkins, Ian A. Wilson, Hang Yin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1128-1140
Number of pages13
JournalCell Reports
Volume17
Issue number4
DOIs
StatePublished - 18 Oct 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 The Author(s)

Keywords

  • HMGB1
  • Toll-like receptors
  • cytokines
  • inflammation
  • pain

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