| First Author | Cui X | Year | 2019 |
| Journal | Am J Physiol Renal Physiol | Volume | 317 |
| Issue | 1 | Pages | F90-F98 |
| PubMed ID | 31091120 | Mgi Jnum | J:280718 |
| Mgi Id | MGI:6369503 | Doi | 10.1152/ajprenal.00017.2019 |
| Citation | Cui X, et al. (2019) Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study. Am J Physiol Renal Physiol 317(1):F90-F98 |
| abstractText | 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-1beta, IL-6, and TNF-alpha. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-alpha, 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-1beta, IL-6, and TNF-alpha as well as reduced spinal expression of mRNAs for IL-6, TNF-alpha, 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. |
