Therapeutic effect of modulating the NLRP3-regulated transforming growth factor-β signaling pathway on interstitial...

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-β (TGF-β)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Lipopolysaccharide (LPS) and protamine sulfate (LPS/PS) were instilled into the mouse bladder twice a week for 5 consecutive weeks to establish a chronic inflammation-induced IC/BPS model (LPS/PS model). Following LPS/PS treatment, curcumin (oral, 100 mg/kg; a potent NLRP3 modulator) was administered for 2 weeks in the curcumin treatment group, and normal saline was used for the sham group. Bladder function was evaluated by performing the voiding spot assay and examining the status of urothelial denudation and fibrosis in bladder tissues. The expression of NLRP3 inflammasome, interleukin-1β, TGF-β, Smad, vimentin, and E-cadherin in bladder tissues was evaluated through immunohistochemistry staining. Results revealed that the repeated instillation of LPS/PS leads to voiding dysfunction, bladder urothelium denudation, and detrusor muscle fibrosis through the upregulation of the NLRP3 inflammasome/IL-1β-related TGF-β/Smad pathway and the increased epithelial-mesenchymal transition process in bladder tissues. The downregulation of the NLRP3 inflammasome/IL-1β-related TGF-β/Smad pathway in bladder tissues through curcumin effectively mitigated bladder injury in the LPS/PS model. In conclusion, the NLRP3 inflammasome/IL-1β-related TGF-β/Smad pathway plays a crucial role in bladder injury in the LPS/PS model, and modulation of this pathway, such as by using curcumin, can effectively mitigate the sequelae of chronic inflammation-induced IC/BPS.