HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

Highlights

• HMGB1 is identified as a DAMP molecule for TLR5, along with TLR2 and TLR4

• HMGB1-induced TLR5 activation causes pain

• The C-terminal acidic tail of HMGB1 is involved in HMGB1-TLR5 interaction

Summary

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.