Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4.

Area of Science:

• Urology
• Pain research
• Molecular biology

Background:

• Bladder pain is a significant symptom in various urological conditions.
• The role of high mobility group box-1 (HMGB1) in bladder pain, particularly its redox states, remains unclear.
• Understanding HMGB1's mechanism is crucial for non-pathological bladder pain.

Purpose of the Study:

• To investigate the distinct effects of disulfide and all-thiol HMGB1 on bladder pain.
• To determine the role of Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) in HMGB1-induced bladder pain.

Main Methods:

• Intravesical administration of specific HMGB1 redox forms in female C57BL/6 mice.
• Assessment of abdominal mechanical hypersensitivity, micturition changes, and bladder inflammation.
• Evaluation of TLR4 and RAGE antagonists (TAK-242 and FPS-ZM1) for systemic and local administration.

Main Results:

• Disulfide HMGB1, but not all-thiol HMGB1, induced mechanical hypersensitivity.
• Both HMGB1 forms caused micturition changes and mild bladder inflammation at high doses.
• Systemic administration of TLR4 or RAGE antagonists, and local TLR4 antagonist, prevented hypersensitivity.

Conclusions:

• The disulfide form of HMGB1 directly mediates bladder pain via TLR4 activation in the bladder.
• This mechanism is independent of secondary inflammation or injury.
• Toll-like receptor 4 (TLR4) presents a specific local therapeutic target for bladder pain.