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Am J Physiol Renal Physiol. 2019 Jul 1;317(1):F90-F98. doi: 10.1152/ajprenal.00017.2019. Epub 2019 May 15.

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

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Department of Urology, University of Iowa , Iowa City, Iowa.
Department of Psychological and Brain Sciences, University of Iowa , Iowa City, Iowa.
Department of Obstetrics and Gynecology, University of Iowa , Iowa City, Iowa.
Department of Anesthesiology, University of Michigan , Ann Arbor, Michigan.
Department of Radiology, University of Iowa , Iowa City, Iowa.
Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama.


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.


Multidisciplinary Approach to the Study of Chronic Pelvic Pain; Toll-like receptor 4; cystitis; model; pain

[Available on 2020-07-01]

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