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Papers of the Week

Papers: 11 May 2019 - 17 May 2019

Animal Studies

2019 Jul 01

Am J Physiol Renal Physiol



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


Cui X, Jing X, Lutgendorf SK, Bradley CS, Schrepf A, Erickson BA, Magnotta VA, Ness TJ, Kreder KJ, O'Donnell MA, Luo Y
Am J Physiol Renal Physiol. 2019 Jul 01; 317(1):F90-F98.
PMID: 31091120.


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 published human studies indicated that IC/BPS patients present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In this study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in IC/BPS patients 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 interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNF)-a. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-a, glial activation markers CD11b and glial fibrillary acidic protein (GFAP), and endogenous TLR4 ligand high mobility group box 1 (HMGB1) was also observed after cystitis induction. Compared to URO-OVA mice, URO-OVA (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-1b, IL-6 and TNF-a as well as reduced spinal expression of mRNAs for IL-6, TNF-a, CD11b, GFAP, and HMGB1. 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 a therapeutic target for IC/BPS pain.