Extracellular high-mobility group box 1 protein (HMGB1) as a mediator of persistent pain

Abstract

Although originally described as a highly conserved nuclear protein, high-mobility group box 1 protein (HMGB1) has emerged as a danger-associated molecular pattern molecule protein (DAMP) and is a mediator of innate and specific immune responses. HMGB1 is passively or actively released in response to infection, injury and cellular stress, providing chemotactic and cytokine-like functions in the extracellular environment, where it interacts with receptors such as receptor for advanced glycation end products (RAGE) and several Toll-like receptors (TLRs). Although HMGB1 was first revealed as a key mediator of sepsis, it also contributes to a number of other conditions and disease processes. Chronic pain arises as a direct consequence of injury, inflammation or diseases affecting the somatosensory system and can be devastating for the affected patients. Emerging data indicate that HMGB1 is also involved in the pathology of persistent pain. Here, we give an overview of HMGB1 as a proinflammatory mediator, focusing particularly on the role of HMGB1 in the induction and maintenance of hypersensitivity in experimental models of pain and discuss the therapeutic potential of targeting HMGB1 in conditions of chronic pain.

Figure 1

HMGB1 induces pain-like behavior in rodents. (A) Injection of recombinant HMGB1 to the paw, ankle joint, sciatic nerve or intrathecal space evokes pain-like behavior in rodents. (B) The structure of HMGB1 with the two DNA binding domains (the A and B boxes), the acidic C-terminal tail and nuclear location signals (NLSs) outlined. The three cysteine residues that are important for functional activity of HMGB1 are highlighted. (C) Graph shows that intraarticular (i.a.) injection of 1 μg disulfide HMGB1, but not saline, induces mechanical hypersensitivity in male Balb/c mice 6 h after injection. Mechanical sensitivity is assessed by von Frey filaments, and data are presented as threshold (g) with 50% probability of response. Data represents mean ± standard error of the mean. n = 5/group. **p < 0.001.