Covarrubias Claudia, Mossa Abubakr H, Yan Laura R, Desormeau Benjamin, Cammisotto Philippe G, Saragovi H Uri, Campeau Lysanne
Lady Davis Institute, McGill University, Montreal, QC H3T 1E2, Canada.
Urology Department, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Life (Basel). 2025 Jun 14;15(6):957. doi: 10.3390/life15060957.
Recurrent bacterial cystitis in women can lead to interstitial cystitis or bladder pain syndrome (IC/BPS). Activation of Toll-like receptor 4 (TLR4) by LPS can upregulate signaling of the pro-inflammatory receptor p75. The aim of the presented study was to assess whether p75 antagonist THX-B can modulate LPS-mediated inflammation in bladder cells. In vitro expression and LPS-activation of p75 were confirmed in urothelial (URO) and smooth muscle (SMC) cells. In UROs, p75 antagonism abolished the LPS-elicited rise in membrane-bound and soluble TNF-α. However, it could not prevent LPS-induced rise in phosphorylated ERK nor decrease in phosphorylated p38MAPK, nor the increase in iNOS and nitric oxide (NO) content. On the other hand, in SMCs, LPS increased phosphorylation of JNK, nuclear translocation of NF-κB, and association of TRAF6 to p75, outcomes prevented by p75 antagonism. In UROs, LPS decreased the expression of tight junction proteins, ZO-1 and occludin, with the latter rescued by p75 antagonism. Intraurethral instillation of LPS increased inflammation in the lamina propria, activation of JNK, and contractile activity of bladder tissue. Alternatively, intraperitoneal THX-B injections prevented LPS-induced inflammation but not enhanced muscle contraction. Our results suggest that inhibition of p75 could help in reducing bladder symptoms during cystitis.
女性复发性细菌性膀胱炎可导致间质性膀胱炎或膀胱疼痛综合征（IC/BPS）。脂多糖（LPS）激活Toll样受体4（TLR4）可上调促炎受体p75的信号传导。本研究的目的是评估p75拮抗剂THX-B是否能调节膀胱细胞中LPS介导的炎症。在上皮细胞（URO）和平滑肌细胞（SMC）中证实了p75的体外表达和LPS激活。在URO细胞中，p75拮抗作用消除了LPS引起的膜结合型和可溶性肿瘤坏死因子-α（TNF-α）的升高。然而，它不能阻止LPS诱导的磷酸化细胞外信号调节激酶（ERK）升高，也不能阻止磷酸化p38丝裂原活化蛋白激酶（p38MAPK）降低，也不能阻止诱导型一氧化氮合酶（iNOS）和一氧化氮（NO）含量增加。另一方面，在SMC细胞中，LPS增加了应激活化蛋白激酶（JNK）的磷酸化、核因子κB（NF-κB）的核转位以及肿瘤坏死因子受体相关因子6（TRAF6）与p75的结合，而p75拮抗作用可阻止这些结果。在URO细胞中，LPS降低了紧密连接蛋白闭锁小带蛋白1（ZO-1）和闭合蛋白的表达，而p75拮抗作用可挽救闭合蛋白的表达。尿道内灌注LPS可增加固有层炎症、JNK激活和膀胱组织的收缩活性。另外，腹腔注射THX-B可预防LPS诱导的炎症，但不能增强肌肉收缩。我们的结果表明，抑制p75有助于减轻膀胱炎期间的膀胱症状。
