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Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain
Shaojing Ye1, Fei Ma1, Dlovan F D Mahmood1
1Research & Development, Lexington VA Health Care System, Lexington, KY, United States of America.
Background:
Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo.
Methodology/Principal Findings:
We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary human urothelial cells) and on PAR4-induced bladder hyperalgesia in vivo (mice). In mice, PAR4 induced HMGB1 release and bladder hyperalgesia through activation of intravesical MIF receptors, CD74 and CXCR4. CXCR2 was not involved in these effects. In primary urothelial cells, PAR4-induced HMGB1 release through activation of CD74 receptors. Micturition parameters in mice were not changed by any of the treatments.
Conclusions/Significance:
Urothelial MIF receptors CD74 and CXCR4 mediate bladder pain through release of urothelial HMGB1. This mechanism may set up persistent pain loops in the bladder and warrants further investigation. Urothelial CD74 and CXCR4 may provide novel targets for interrupting bladder pain.
Insights
Activation of protease activated receptor 4 (PAR4) in the bladder triggers macrophage migration inhibitory factor (MIF) release, leading to bladder pain. Urothelial MIF receptors CD74 and CXCR4 mediate this pain via high mobility group box-1 (HMGB1) release.
Area of Science:
- Urology
- Immunology
- Pain Research
Background:
- Protease activated receptor 4 (PAR4) activation in the bladder initiates a cascade involving macrophage migration inhibitory factor (MIF).
- MIF binds to urothelial receptors, subsequently releasing high mobility group box-1 (HMGB1) and causing bladder hyperalgesia.
- The specific roles of individual urothelial MIF receptors in this process were not fully understood.
Purpose of the Study:
- To investigate the contribution of individual urothelial MIF receptors (CD74, CXCR4, CXCR2) to PAR4-induced HMGB1 release.
- To determine the role of these receptors in PAR4-mediated bladder pain.
- To explore potential therapeutic targets for bladder pain.
Main Methods:
- Utilized in vivo mouse models and in vitro primary human urothelial cell cultures.
- Administered intravesical MIF or MIF receptor antagonists.
- Assessed PAR4-induced HMGB1 release and bladder hyperalgesia.
Main Results:
- PAR4 induced HMGB1 release and bladder hyperalgesia via CD74 and CXCR4 activation in vivo.
- CXCR2 was not implicated in PAR4-induced effects.
- In vitro, PAR4-induced HMGB1 release was mediated by CD74 activation.
- No significant changes in micturition parameters were observed.
Conclusions:
- Urothelial MIF receptors CD74 and CXCR4 are key mediators of bladder pain through HMGB1 release.
- This pathway may contribute to persistent bladder pain loops.
- Targeting urothelial CD74 and CXCR4 presents a potential strategy for bladder pain management.
