Role of macrophage–derived HMGB1 as an algogenic molecule ⁄ therapeutic target in visceral pain

Abstract

Accumulating evidence sheds light on the crucial role of a neuroimmune crosstalk in neurogenic inflammation and diverse neurological diseases associated with neuro inflammation. High mobility group box 1 (HMGB 1 ), one of damage–associated molecular patterns (DAMPs) ⁄ alarmins, is now considered a pro–inflammatory ⁄ pro– nociceptive molecule, and participates in the pathogenesis of neuropathic and inflammatory pain. In this review, we focus on the role of HMGB 1 in visceral pain signaling in the bladder, pancreas and colon. In rodent models for cystitis–related bladder pain, macrophage–derived HMGB 1 activates the receptor for advanced glycation end– products (RAGE), and induces NF– κ B–dependent overexpression of cystathionine– γ –lyase, an H 2 S–generating enzyme, resulting in excessive excitation of nociceptors through the H 2 S ⁄ Ca v 3 . 2 T–type calcium channel pathway and subsequent bladder pain. The macrophage–derived HMGB 1 also appears to play a role in the development of pancreatic pain accompanying acute pancreatitis and of colonic pain in a mouse model for irritable bowel syndrome (IBS). Thus, HMGB 1 is considered a key mediator for a neuroimmune crosstalk involved in visceral pain signaling in the bladder, pancreas and colon, and may serve as a novel therapeutic target for treatment of visceral pain in patients with interstitial cystitis ⁄ bladder pain syndrome, acute pancreatitis or IBS.