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.

Pattern recognition receptors in chronic pain: Mechanisms and therapeutic implications

“…The administration of a RAGE-neutralizing antibody suppressed all-thiol HMGB1-dependent neuronal excitation in vitro. Moreover, intraperitoneal injection of the RAGE-neutralizing antibody reversed mechanical hypersensitivity induced by tibial nerve injury in rats, supporting a role for RAGE in pathological pain (Allette et al, 2014).…”

“…RAGE mRNA and protein expression has been identified in rat primary DRG neurons (Allette et al, 2014;Saleh et al, 2013;Vincent et al, 2007). Weak RAGE immunoreactivity has been observed in intact peripheral nerve axons, DRG neuronal cell bodies and spinal nerve bundles in rodents and following peripheral nerve injury and experimental models of diabetes, RAGE is upregulated in these sites (Juranek et al, 2013;Rong et al, 2004b;Shibasaki et al, 2010).…”

“…Two recent studies have demonstrated that blocking RAGE might serve as a novel therapeutic target for the management of chronic pain. A single application of monoclonal antibody against RAGE reverses established mechanical allodynia induced by tibial nerve injury in rats (Allette et al, 2014). Low molecular weight heparin, which is known to inhibit RAGE, attenuated the cyclophosphamideinduced bladder pain and referred hyperalgesia in mice (Tanaka et al, 2014).…”

“…PNS neuron rodents TLR3, 4, 5 7, RAGE (in vitro) TLR3,4,5,7,9, RAGE (in vitro) (Allette et al, 2014;Goethals et al, 2010;Park et al, 2014;Qi et al, 2011;Saleh et al, 2013) TLR3, 4, 5, 7, RAGE a (in vivo) (Allette et al, 2014;Barajon et al, 2009;Juranek et al, 2013;Rong et al, 2004a;Saleh et al, 2013;Shibasaki et al, 2010;Vincent et al, 2007) human TLR3, 7, 9 (in vitro) (Qi et al, 2011) RAGE a (in vivo) TLR4 a , RAGE a (in vivo) (Bierhaus et al, 2004;Sousa et al, 2001;Wadachi and Hargreaves, 2006) Schwann cell rodents TLR1-9 (in vitro) TLR3, 4, RAGE (in vitro) (Colomar et al, 2003;Goethals et al, 2010;Lee et al, 2007;Perrone et al, 2008) RAGE a (in vivo) (Shibasaki et al, 2010) human TLR2 (in vitro) (Oliveira et al, 2003) TLR2 a , RAGE a (in vivo) (Oliveira et al, 2003;Sousa et al, 2001) microglia rodents TLR1-9, RAGE (in vitro) TLR2, 3, 4, 6, 7, 9, RAGE (in vitro) (Alarcon et al, 2005;Butchi et al, 2010;DukicStefanovic et al, 2003;Jiang et al, 2014;Kielian et al, 2002;Lehnardt et al, 2003;Olson and Miller, 2004;Pan et al, 2011;…”

The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction

“…However as the half-life of this isoform is relatively short, the disulfide form of HMGB1 may also contribute to organ dysfunction and changes in blood-brain permeability in a TLR4 dependent manner (78,125,139). Subsequently, HMGB1 isoforms present in injury conditions may suitably act as priming signals which are perceived in both the nervous and immune system (3,38,109,120). This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction.…”