Manuel Robbie Sj, Rundquist Allison, Ambrogi Marcela, Scharpf Brandon R, Peterson Nelson T, Sandhu Jaskiran K, Chandrashekar Sneha, Ridlon Monica, Crawford Latasha K, Keil-Stietz Kimberly P, Peterson Richard E, Vezina Chad M
Department of Comparative Biosciences, University of Wisconsin-Madison Madison, WI, USA.
Molecular and Environmental Toxicology Graduate Program, University of Wisconsin School of Medicine and Public Health Madison, WI, USA.
Am J Clin Exp Urol. 2024 Aug 25;12(4):149-161. doi: 10.62347/PEGK4888. eCollection 2024.
Prostate inflammation is linked to lower urinary tract dysfunction and is a key factor in chronic prostatitis/chronic pelvic pain syndrome. Autoimmunity was recently identified as a driver of prostate inflammation. Agonists of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, have been used to suppress autoimmunity in mouse models of colitis, rhinitis, and dermatitis, but whether AHR agonists suppress prostate autoimmunity has not been examined. Here, we test whether ITE (2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester), an AHR agonist, suppresses inflammation, allodynia, and urinary dysfunction in a mouse model of experimental autoimmune prostatitis (EAP).
C57BL/6J adult male mice were immunized with rat prostate antigen to induce EAP or TiterMax Gold® adjuvant (uninflamed control). Mice were also treated with ITE (10 mg/kg/day IP) or DMSO (vehicle, 5 mg/kg/day IP) for 6 days. Using the Nanostring nCounter Inflammation Panel, we evaluated the impact of EAP and ITE on prostatic RNA abundance. We validated EAP and ITE-mediated changes in a subset of RNAs by RT-PCR and RNAScope RNA detection.
EAP appeared to heighten histological inflammation in the dorsal prostate, induced tactile allodynia, and appeared to increase the frequency of non-voiding bladder contractions. ITE mitigated some actions of EAP. EAP changed abundance of 40 inflammation-related RNAs, while ITE changed abundance of 28 inflammation-related RNAs. We identified a cluster of RNAs for which ITE protected against EAP-induced changes in the abundance of , , and . ITE also increased the abundance of the AHR-responsive RNA.
These findings support the hypothesis that ITE activates the AHR in the prostate and reduces autoimmune-mediated prostatitis in mice.
前列腺炎症与下尿路功能障碍有关，是慢性前列腺炎/慢性盆腔疼痛综合征的关键因素。自身免疫最近被确定为前列腺炎症的驱动因素。芳烃受体（AHR）是一种配体激活的转录因子，其激动剂已被用于抑制结肠炎、鼻炎和皮炎小鼠模型中的自身免疫，但AHR激动剂是否能抑制前列腺自身免疫尚未得到研究。在此，我们测试AHR激动剂2-（1'H-吲哚-3'-羰基）-噻唑-4-羧酸甲酯（ITE）是否能抑制实验性自身免疫性前列腺炎（EAP）小鼠模型中的炎症、痛觉过敏和排尿功能障碍。
用大鼠前列腺抗原免疫C57BL/6J成年雄性小鼠以诱导EAP或使用TiterMax Gold®佐剂（未发炎对照）。小鼠还接受ITE（10 mg/kg/天，腹腔注射）或二甲基亚砜（载体，5 mg/kg/天，腹腔注射）治疗6天。使用Nanostring nCounter炎症检测板，我们评估了EAP和ITE对前列腺RNA丰度的影响。我们通过逆转录聚合酶链反应（RT-PCR）和RNAscope RNA检测验证了EAP和ITE介导的部分RNA变化。
EAP似乎加剧了背侧前列腺的组织学炎症，诱发触觉痛觉过敏，并似乎增加了非排尿膀胱收缩的频率。ITE减轻了EAP的一些作用。EAP改变了40种炎症相关RNA的丰度，而ITE改变了28种炎症相关RNA的丰度。我们鉴定出一组RNA，ITE可防止EAP诱导其丰度发生变化。ITE还增加了AHR反应性RNA的丰度。
这些发现支持以下假设，即ITE激活前列腺中的AHR并减少小鼠自身免疫介导的前列腺炎。
