POL Scientific / Bladder / Volume 11 / Issue 2 / DOI: 10.14440/bladder.2024.0015
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RESEARCH ARTICLE

Modulation of persistent bladder pain in mice: The role of macrophage migration inhibitory factor, high mobility group box-1, and downstream signaling pathways

Shaojing Ye1 ,  Fei Ma1 ,  Dlovan F.D. Mahmood1 ,  Pedro L. Vera1,2*
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1 Lexington VA Health Care System, Research and Development, Lexington, KY, USA
2 Department of Physiology, School of Medicine, University of Kentucky, Lexington, KY, USA
Bladder 2024 , 11(2), e21200011; https://doi.org/10.14440/bladder.2024.0015
Submitted: 10 July 2024 | Revised: 15 August 2024 | Accepted: 14 September 2024 | Published: 28 October 2024
© 2024 by the Bladder published by POL Scientific. Licensee POL Scientific, USA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Background: Repeated intravesical activation of protease-activated receptor-4 (PAR4) serves as a model of persistent bladder hyperalgesia (BHA) in mice, which lasts several days after the final stimulus. Spinal macrophage migration inhibitory factor (MIF) and high mobility group box 1 (HMGB1) are critical mediators in the persistence of BHA. Objective: We aimed to identify effective systemic treatments for persistent BHA using antagonists or transgenic deletions. Methods: Persistent BHA was induced through transurethral instillations of a PAR4-activating peptide (PAR4-AP; 100 μM, 1 h; scrambled peptide, control) under anesthesia, administered on Days 0, 2, and 4. Lower abdominal hypersensitivity was measured on Days 0–4 and 7–9. Systemic injections from Days 2–8 included ISO-1 (a MIF antagonist), ethyl pyruvate (an inhibitor of HMGB1 release), phosphate-buffered saline, or 10% DMSO (vehicle control) in C57BL/6 mice. To examine the role of HMGB1 receptors, Toll-like receptor-4 (TLR4)-null mice or systemic treatment with FPS-ZM1 (receptor for advanced glycation end product [RAGE] antagonist) were used. In addition, TIR-domain-containing adaptor-inducing interferon-β (TRIF)-null mice were tested to assess the involvement of TLR4 signaling pathways. Micturition volume and frequency were assessed on Day 9, and the bladder was histopathologically examined to assess inflammation and edema. Results: MIF antagonism significantly reversed persistent BHA, whereas HMGB1 antagonism led to a partial reduction of persistent BHA. TLR4 deficiency or systemic administration of FPS-ZM1 significantly mitigated persistent BHA, while TRIF-deficient mice experienced a faster onset of BHA. Only MIF or HMGB1 inhibition resulted in increased micturition volume. The histopathological examination revealed no changes in inflammation or edema. Conclusion: MIF and HMGB1, acting through TLR4 and RAGE, mediated persistent BHA, while TRIF might modulate its onset. Further exploration of downstream TLR4 signaling may uncover novel therapeutic targets for treating persistent bladder pain.

Keywords
Macrophage migration inhibitory factor
High mobility group box-1
Toll-like receptor-4
RAGE
Bladder pain
Funding
This research was supported by funding from the NIH (DK121695; PLV).
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Conflict of interest
The authors declare no conflicts of interest.
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