title: HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia.
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.
authors.affiliation: Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Das
authors.affiliation: Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Dewan
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Grace
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Gunn
authors.affiliation: Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Ryo
authors.initials: R
authors.lastname: Tamura
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Netanel
authors.initials: N
authors.lastname: Tzarum
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA. Electronic address: hubert.yin@colorado.edu.
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016207:Cytokines / Q000096:biosynthesis; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D016328:NF-kappa B; D051198:Toll-Like Receptor 5; D009569:Nitric Oxide
keywords: HMGB1; Toll-like receptors; cytokines; inflammation; pain