Norepinephrine as the Intrinsic Contributor to Contact Lens-Induced Pseudomonas aeruginosa Keratitis.
Norepinephrine as the Intrinsic Contributor to Contact Lens-Induced Pseudomonas aeruginosa Keratitis.
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DOI：
10.1167/iovs.64.5.26
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发表时间：
2023-05-01
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
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接触透镜配戴（CLW）是铜绿假单胞菌角膜炎（PAK）的主要危险因素之一。然而，导致CLW期间角膜炎高易感性的内在因素仍有待阐明。长期CLW可升高角膜去甲肾上腺素（NE）浓度。在这项研究中，我们研究了NE在促进PAK中的作用。我们构建了损伤诱导的PAK模型和CLW诱导的PAK模型，以证实NE在角膜感染过程中的影响。用NE的药理学阻断和基因敲低小鼠研究NE的下游效应。进行RNA测序以探索NE处理期间的细胞变化。采用非参数Mann-Whitney U检验或Kruskal-Wallis检验来确定显著性（P < 0.05）。在CLW过程中，即使没有人工角膜损伤，补充NE也会导致PAK。其作用是由角膜上皮细胞的β2-肾上腺素能受体（β2-AR）介导的。用NE拮抗剂ICI 118，551（ICI）阻断β2-AR或删除其编码基因Adrb 2可显著减轻CLW期间的感染。相反，β2-AR激活损害了上皮的完整性，并显著增加了皮质斑块标记物ezrin。转录组分析表明ICI对角膜炎的保护作用是通过双特异性磷酸酶介导的。Dusp 5拮抗剂Suramin可阻断ICI的保护作用。这些数据揭示了NE作为一种内在因子促进CLW诱导的PAK的新机制，并为通过靶向NE-β2-AR治疗角膜炎提供了新的治疗靶点。
Contact lens wear (CLW) is one of the leading risk factors for Pseudomonas aeruginosa keratitis (PAK). However, the intrinsic factors that contribute to the high susceptibility to keratitis during CLW remain to be elucidated. CLW over an extended period can elevate corneal norepinephrine (NE) concentration. In this study, we investigated the role of NE in promoting PAK. We constructed an injury-induced PAK model and a CLW-induced PAK model to confirm the impact of NE during corneal infection. Pharmacological blockage of NE and gene knockdown mouse were used to investigate the downstream effector of NE. RNA sequencing was performed to explore the cellular alterations during NE treatment. Non-parametric Mann-Whitney U test or Kruskal-Wallis test were used to ascertain the significance (P < 0.05). Supplementation of NE led to PAK even without artificial corneal injury during CLW. The effect was mediated by the β2-adrenergic receptor (β2-AR) in the corneal epithelium. The β2-AR blockage by the NE antagonist ICI118,551 (ICI) or by deleting of its encoding gene Adrb2 significantly alleviated infection during CLW. Conversely, β2-AR activation compromised the integrity of the epithelium and significantly increased the cortical plaque marker ezrin. Transcriptome analysis identified that the protective effect of ICI on the keratitis was mediated by dual-specificity phosphatases. Suramin, a Dusp5 antagonist, abrogated the protective effect of ICI. These data reveal a new mechanism by which NE acts as an intrinsic factor that promotes CLW-induced PAK and provide novel therapeutic targets for treating keratitis by targeting NE-β2-AR.
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影响因子：
3
作者：
Liu, Guoying;Li, Tan;Qi, Benxiang;Gong, Ganyu;Guo, Tengyou;Zhou, Qingjun;Jhanji, Vishal;Zhang, Bi Ning;Du, Xianli
通讯作者：
Du, Xianli
影响因子：
4.2
作者：
Enzor, Rikki;Bowers, Eve M. R.;Jhanji, Vishal
通讯作者：
Jhanji, Vishal
影响因子：
2.8
作者：
Forte, Raimondo;Cennamo, Gilda;Del Prete, Antonio
通讯作者：
Del Prete, Antonio
影响因子：
3.6
作者：
Hoffmann, C;Leitz, MR;Klotz, KN
通讯作者：
Klotz, KN
影响因子：
56.9
作者：
Luttrell, LM;Ferguson, SSG;Lefkowitz, RJ
通讯作者：
Lefkowitz, RJ