Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study.

Abstract

Altered Toll-like receptor (TLR)4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis/bladder pain syndrome (IC/BPS). Our previously published human studies indicated that patients with IC/BPS present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In the present study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in patients with IC/BPS using our validated IC/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines IL-1β, IL-6, and TNF-α. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-α, glial activation markers CD11b and glial fibrillary acidic protein, and endogenous TLR4 ligand high mobility group box 1 was also observed after cystitis induction. Compared with URO-OVA mice, TLR4-deficient URO-OVA mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4-selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1β, IL-6, and TNF-α as well as reduced spinal expression of mRNAs for IL-6, TNF-α, CD11b, glial fibrillary acidic protein, and high mobility group box 1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and therapeutic target for IC/BPS pain.

• Authors: Xiangrong Cui, Xuan Jing, Susan K Lutgendorf, Catherine S Bradley, Andrew Schrepf, Bradley A Erickson, Vincent A Magnotta, Timothy J Ness, Karl J Kreder, Michael A O'Donnell, Yi Luo
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 317 Issue 1 Pg. F90-F98 (07 01 2019) ISSN: 1522-1466 [Electronic] United States
• PMID: 31091120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics
• Cytokines
• Inflammation Mediators
• Sulfonamides
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
• Ovalbumin

Topics

• Analgesics (pharmacology)
• Animals
• Autoimmune Diseases (genetics, immunology, metabolism, physiopathology)
• Cells, Cultured
• Cystitis, Interstitial (genetics, immunology, metabolism, physiopathology)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Inflammation Mediators (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Nociceptive Pain (genetics, immunology, metabolism, physiopathology)
• Ovalbumin (genetics, immunology, metabolism)
• Pain Threshold (drug effects)
• Signal Transduction
• Spine (immunology, metabolism)
• Spleen (immunology, metabolism)
• Sulfonamides (pharmacology)
• Toll-Like Receptor 4 (antagonists & inhibitors, genetics, immunology, metabolism)
• Urinary Bladder (drug effects, immunology, metabolism, physiopathology)
• Urodynamics