Hsiang Harrison W, Girard Beatrice M, Vizzard Margaret A
The Larner College of Medicine at The University of Vermont, Department of Neurological Sciences, Burlington, VT, United States.
Front Urol. 2023;2. doi: 10.3389/fruro.2022.1089220. Epub 2023 Jan 26.
IC/BPS is a chronic inflammatory pelvic pain syndrome characterized by lower urinary tract symptoms including unpleasant sensation (pain, pressure, or discomfort) in the suprapubic or bladder area, as well as increased urinary frequency and urgency, and decreased bladder capacity. While its etiology remains unknown, increasing evidence suggests a role for changes in nerve growth factor (NGF) signaling. However, NGF signaling is complex and highly context dependent. NGF activates two receptors, TrkA and p75, which activate distinct but overlapping signaling cascades. Dependent on their coexpression, p75 facilitates TrkA actions. Here, we show effects of CYP treatment and pharmacological inhibition of p75 (via LM11A-31) and TrkA (ARRY-954) on NGF signaling-related proteins: NGF, TrkA, phosphorylated (p)-TrkA, p75, p-ERK1/2, and p-JNK. Cystitis conditions were associated with increased urothelial NGF expression and decreased TrkA and p75 expression as well as altering their co-expression ratio; phosphorylation of ERK1/2 and JNK were also altered. Both TrkA and p75 inhibition affected the activation of signaling pathways downstream of TrkA, supporting the hypothesis that NGF actions during cystitis are primarily TrkA-mediated. Our findings, in tandem with our recent companion paper demonstrating the effects of TrkA, TrkB, and p75 inhibition on bladder function in a mouse model of cystitis, highlight a variety of potent therapeutic targets and provide further insight into the involvement of NGF signaling in sustained conditions of bladder inflammation.
间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种慢性炎症性盆腔疼痛综合征，其特征为下尿路症状，包括耻骨上或膀胱区域的不适感（疼痛、压迫感或不适），以及尿频、尿急增加和膀胱容量减少。虽然其病因尚不清楚，但越来越多的证据表明神经生长因子（NGF）信号通路的变化起了作用。然而，NGF信号通路很复杂，且高度依赖于环境。NGF激活两种受体，TrkA和p75，它们激活不同但重叠的信号级联反应。取决于它们的共表达情况，p75促进TrkA的作用。在这里，我们展示了环磷酰胺（CYP）处理以及对p75（通过LM11A-31）和TrkA（ARRY-954）进行药理学抑制对NGF信号相关蛋白的影响：NGF、TrkA、磷酸化（p）-TrkA、p75、p-ERK1/2和p-JNK。膀胱炎状态与尿路上皮NGF表达增加、TrkA和p75表达减少以及它们的共表达比例改变有关；ERK1/2和JNK的磷酸化也发生了改变。TrkA和p75的抑制均影响TrkA下游信号通路的激活，支持了膀胱炎期间NGF作用主要由TrkA介导的假说。我们的研究结果，与我们最近的一篇姊妹论文相结合，该论文证明了在膀胱炎小鼠模型中TrkA、TrkB和p75抑制对膀胱功能的影响，突出了多种有效的治疗靶点，并进一步深入了解了NGF信号通路在膀胱炎症持续状态中的作用。
