Spinal high‐mobility group box‐1 induces long‐lasting mechanical hypersensitivity through the toll‐like receptor 4 and upregulation of interleukin‐1β in activated astrocytes

• Published in: Journal of neurochemistry 2019-09, Vol.150 (6), p.738-758
• Main Authors: Morioka, Norimitsu, Miyauchi, Kazuki, Miyashita, Keita, Kochi, Takahiro, Zhang, Fang Fang, Nakamura, Yoki, Liu, Keyue, Wake, Hidenori, Hisaoka‐Nakashima, Kazue, Nishibori, Masahiro, Nakata, Yoshihiro
• Format: Article
• Language: English
• Subjects: Activation; allodynia; Animals; Antibodies; Astrocytes; Astrocytes - metabolism; Chemokines; Cytokines; Gabapentin; Glial cells; glutamate; Glutamatergic transmission; Glycosylation; HMGB1; HMGB1 protein; HMGB1 Protein - metabolism; Hyperalgesia - metabolism; Hypersensitivity; Inhibitors; Interleukin-1beta - metabolism; Interleukins; interleukin‐1β; Male; Mechanical stimuli; Mice; Mobility; Neuralgia; Neuralgia - metabolism; neuropathic pain; Pain; Pain perception; Sciatic nerve; Spinal Cord - metabolism; TLR4; TLR4 protein; TLR5 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Up-Regulation
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14812

Intrathecal treatment with recombinant high‐mobility group box‐1 (rHMGB1) in naïve mice leads to a persistent and significantly decreased hind paw withdrawal threshold to mechanical stimuli, suggesting that spinal HMGB1 evokes abnormal pain processing. By contrast, repeated intrathecal treatment with anti‐HMGB1 antibody significantly reverses hind paw mechano‐hypersensitivity in mice with a partial sciatic nerve ligation (PSNL). By contrast, the cellular mechanism by which spinal HMGB1 induces neuropathic pain has yet to be fully elaborated. The current study tested the hypothesis that spinal HMGB1 could induce mechanical hypersensitivity through the activation of specific receptor in glial cells. Intrathecal pretreatment with toll‐like receptor (TLR) 4 inhibitors, but not TLR5, receptor for advanced glycation end‐products and C‐X‐C chemokine receptor type 4 inhibitors, prevented rHMGB1‐evoked mechanical hypersensitivity. Activation of spinal astrocytes appears to be crucial for the mechanism of action of rHMGB1 in naïve mice, as intrathecal pretreatment with astrocytic inhibitors prevented the rHMGB1‐induced mechanical hypersensitivity. Interleukin‐1β (IL‐1β) was up‐regulated within activated astrocytes and block of TLR4 prevented the upregulation of IL‐1β. Interleukin‐1β appears to be secreted by activated astrocytes, as IL‐1β neutralizing antibody prevented rHMGB1‐induced mechanical hypersensitivity. Furthermore, intrathecal pretreatment with either MK801 or gabapentin prevented the rHMGB1‐induced mechanical hypersensitivity, suggesting roles for spinal glutamate and the N‐methyl‐d‐aspartate receptor in the mediation of rHMGB1‐induced mechanical hypersensitivity. Thus, the current findings suggest that spinal HMGB1 upregulates IL‐1β in spinal astrocytes through a TLR4‐dependent pathway and increases glutamatergic nociceptive transduction. These spinal mechanisms could be key steps that maintain neuropathic pain. Increased spinal dorsal horn high‐mobility group box‐1 (HMGB1) is involved in the modulation of nociceptive transduction following a peripheral neuropathy. Intrathecal treatment with recombinant HMGB1 (rHMGB1) evokes mechanical hypersensitivity through the activation of spinal astrocytic toll‐like receptor 4 (TLR4). Activated astrocytes upregulate interleukin‐1β (IL‐1β) expression, which in turn evokes mechanical hypersensitivity. Furthermore, spinal glutamate and the N‐methyl‐d‐aspartate receptor are crucial in the HMGB1‐induced mechanical hype