A gatekeeper sympathetic control of lacrimal tear secretion and dry eye onset through the NA-Adra1a-Ucp2 pathway

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-06-05 DOI:10.1038/s41467-025-60476-z

Mingli Qu, Qun Wang, Xiaofei Bai, Jing Feng, Sai Zhang, Yangyang Zhang, Qing Chen, Hai Zhu, Hengrui Zhang, Qunqin Guo, Bin Zhang, Shengqian Dou, Yujie Qiao, Hongwei Wang, Yihai Cao, Lixin Xie, Qingjun Zhou

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Abstract

Tear secretion from the lacrimal gland is essential for maintaining ocular surface homeostasis, and its insufficiency causes aqueous-deficient dry eye. Unlike the well-established parasympathetic neuronal regulation, the role of sympathetic nervous system (SNS) in tear secretion remains controversial. Here, we demonstrate the intact sympathetic innervation in lacrimal gland and its activation under multiple dry eye stresses. Pharmacological, surgical, and genetic blockade of SNS increases tear secretion and alleviates dry eye signs. Mechanistically, SNS-driven noradrenaline (NA) release activates α1a-adrenergic receptor (Adra1a) in acinar and myoepithelial cells to regulate mitochondrial Ucp2 and tear secretion. Systemic and local delivery of Adra1a antagonists, including silodosin and tamsulosin, improves tear secretion and reduces corneal lesions in multiple dry eye mouse models. In addition, we identify the brain locus coeruleus as an upstream driver orchestrating sympathetic regulation of lacrimal secretion. Overall, these findings reveal a gatekeeper role of SNS in tear secretion and offer potential therapeutic strategies for dry eye disease.

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通过NA-Adra1a-Ucp2通路控制泪液分泌和干眼发病的守门人交感神经

泪腺的泪液分泌对维持眼表稳态至关重要，其分泌不足会导致缺水性干眼症。与公认的副交感神经调节不同，交感神经系统（SNS）在泪液分泌中的作用仍然存在争议。在此，我们展示了完整的泪腺交感神经支配及其在多重干眼压力下的激活。药物、手术和遗传阻断SNS可增加泪液分泌，减轻干眼症状。sns驱动的去甲肾上腺素（NA）释放激活腺泡和肌上皮细胞α1a-肾上腺素能受体（Adra1a），调节线粒体Ucp2和泪液分泌。在多种干眼症小鼠模型中，全身和局部递送Adra1a拮抗剂，包括西洛多辛和坦索罗辛，可改善泪液分泌并减少角膜病变。此外，我们确定脑蓝斑是一个上游驱动协调交感调节泪分泌。总之，这些发现揭示了SNS在泪液分泌中的守门人作用，并为干眼病的治疗提供了潜在的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.