Anwar Shehata, Lin Po-Ching Patrick, Pacheco Lazaro, Imai Kazuhiro, Tan Zhengzhong, Song Ziyuan, Wakamatsu Yuki, Minamiya Yoshihiro, Cheng Jianjun, Ko CheMyong, Inoue Makoto
Department of Comparative Biosciences, The University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, IL 61802, USA.
Faculty of Veterinary Medicine, Department of Pathology, Beni-Suef University (BSU), Beni-Suef 62511, Egypt.
PNAS Nexus. 2025 Jan 20;4(1):pgaf010. doi: 10.1093/pnasnexus/pgaf010. eCollection 2025 Jan.
Estrogen, a steroid hormone synthesized by both gonadal and nongonadal tissues, plays a pivotal role in modulating immune responses, including reducing relapse rates in relapsing-remitting multiple sclerosis (MS). This study explored the expression of aromatase, the enzyme responsible for estrogen synthesis, in lymph nodes (LNs) and its potential role in the pathogenesis of MS using a mouse model. We utilized Cyp19-RFP mice where cells that express or have previously expressed the Cyp19 gene (encoding aromatase) are marked by red fluorescent protein (RFP). RFP was detected in the high endothelial venules of all morphologically identifiable LNs, indicating aromatase activity within these tissues. We discovered that LNs actively synthesize 17β-estradiol, but this activity declines with age. Targeted delivery of an aromatase inhibitor specifically to LNs induced an interferon-β-resistant experimental autoimmune encephalomyelitis (EAE) phenotype. This phenotype was accompanied by significant gray matter atrophy in the spinal cord. These findings underscore LNs as crucial sites of de novo 17β-estradiol production, potentially contributing to nonremitting EAE phenotypes. The observed decline in 17β-estradiol likely exacerbates MS pathogenesis in aging mice. Importantly, aromatase expression in human cervical LNs suggests that these sites may similarly contribute to estrogen synthesis in humans, potentially opening new avenues for understanding and treating MS.
雌激素是一种由性腺和非性腺组织合成的甾体激素，在调节免疫反应中起关键作用，包括降低复发缓解型多发性硬化症（MS）的复发率。本研究使用小鼠模型，探讨了负责雌激素合成的芳香化酶在淋巴结（LNs）中的表达及其在MS发病机制中的潜在作用。我们使用了Cyp19-RFP小鼠，其中表达或先前表达过Cyp19基因（编码芳香化酶）的细胞用红色荧光蛋白（RFP）标记。在所有形态可识别的淋巴结的高内皮小静脉中均检测到RFP，表明这些组织内存在芳香化酶活性。我们发现淋巴结可活跃地合成17β-雌二醇，但这种活性会随着年龄的增长而下降。将芳香化酶抑制剂特异性地靶向递送至淋巴结会诱导出一种对干扰素-β有抗性的实验性自身免疫性脑脊髓炎（EAE）表型。这种表型伴有脊髓灰质的显著萎缩。这些发现强调了淋巴结是从头合成17β-雌二醇的关键部位，可能导致持续性EAE表型。观察到的17β-雌二醇水平下降可能会加剧衰老小鼠的MS发病机制。重要的是，人颈部淋巴结中的芳香化酶表达表明，这些部位可能同样对人类雌激素合成有贡献，这可能为理解和治疗MS开辟新途径。
