title: Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain.
abstract: Recent studies indicate that the release of high mobility group box 1 (HMGB1) following nerve injury may play a central role in the pathogenesis of neuropathic pain. HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs). The degree to which HMGB1 activates a receptor is thought to be dependent upon the oxidative state of the ligand, resulting in the functional isoforms of all-thiol HMGB1 (at-HMGB1) acting through RAGE, and disufide HMGB1 (ds-HMGB1) interacting with TLR4. Though it is known that dorsal root ganglia (DRG) sensory neurons exposed to HMGB1 and TLR4 agonists can influence excitation, the degree to which at-HMGB1 signaling through neuronal RAGE contributes to neuropathic pain is unknown. Here we demonstrate that at-HMGB1 activation of nociceptive neurons is dependent on RAGE and not TLR4. To distinguish the possible role of RAGE on neuropathic pain, we characterized the changes in RAGE mRNA expression up to one month after tibial nerve injury (TNI). RAGE mRNA expression in lumbar dorsal root ganglion (DRG) is substantially increased by post-injury day (PID) 28 when compared with sham injured rodents. Protein expression at PID28 confirms this injury-induced event in the DRG. Moreover, a single exposure to monoclonal antibody to RAGE (RAGE Ab) failed to abrogate pain behavior at PID 7, 14 and 21. However, RAGE Ab administration produced reversal of mechanical hyperalgesia on PID28. Thus, at-HMGB1 activation through RAGE may be responsible for sensory neuron sensitization and mechanical hyperalgesia associated with chronic neuropathic pain states.
authors.affiliation: Medical Science Training Program, Department of Anatomy, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Yohance M
authors.initials: YM
authors.lastname: Allette
authors.affiliation: Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Due
authors.affiliation: Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.affiliation: Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Polina
authors.initials: P
authors.lastname: Feldman
authors.affiliation: Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Ripsch
authors.affiliation: Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Pharmacology and Toxicology, United States; Department of Biochemistry and Molecular Biology, United States.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, United States; Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: fawhite@iupui.edu.
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000503:physiopathology; D024243:HMGB1 Protein / Q000378:metabolism*; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium
keywords: Alarmin; DAMP; DRG; Dorsal root ganglia; HMGB1; Pain; RAGE; TLR4