Purpose

Ocular allergy leads to acute and chronic inflammation that may deteriorate the conjunctiva and other ocular tissue. The conjunctiva is covered with abundant lymphatic vessels but how the conjunctival lymphatic system patriciates in the development of allergic eye disease (AED) remains to be elucidated.

Methods and results

By using ovalbumin (OVA)+pertussis toxin (PTX) as a sensitizer followed by daily OVA challenges, we induced optimized AED manifestations in mice. We show that conjunctival lymphatics underwent significant expansion after 28 days of chronic OVA challenge, and this process can be prevented by inducible genetic ablation of lymphatic Vegfr3. Through transcriptomic profile analysis in combination with histopathological examinations, we found that pro-lymphangiogenic VEGFR3 signal promoted allergy-induced activation of T helper 2 (Th2) type immune responses, including antigen presentation, and Th2 cells, B cells and mast cell-related pathways in the conjunctiva, thereby critically contributing to the immunoglobulin E (IgE) production and AED manifestations. As a result, ocular allergy can be alleviated by genetic inhibition of lymphatic Vegfr3. Interestingly, pro-lymphangiogenic VEGFR3 signal did not appear to affect the obstruction of meibomian glands (MGs) or the activation of Th17 type and neutrophil pathways that are associated with AED.

Conclusions

These data reveal the key role of pro-lymphangiogenic VEGFR3 signaling in the development of AED and provide experimental evidence that VEGFR3 inhibition may be useful in treating ocular allergy in patients.

中文翻译：

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通过抑制促淋巴管生成的 VEGFR3 信号减轻实验性过敏性眼病

目的

眼部过敏会导致急性和慢性炎症，可能会使结膜和其他眼部组织恶化。结膜上覆盖着丰富的淋巴管，但结膜淋巴系统如何参与过敏性眼病 (AED) 的发展仍有待阐明。

方法和结果

通过使用卵清蛋白 (OVA) + 百日咳毒素 (PTX) 作为增敏剂，然后每天进行 OVA 挑战，我们在小鼠中诱导了优化的 AED 表现。我们表明，在慢性 OVA 攻击 28 天后，结膜淋巴管经历了显着扩张，并且可以通过淋巴管Vegfr3的诱导基因消融来阻止这一过程。通过转录组学分析结合组织病理学检查，我们发现促淋巴管生成的 VEGFR3 信号促进过敏诱导的 T 辅助细胞 2 (Th2) 型免疫反应的激活，包括抗原呈递，以及结膜中的 Th2 细胞、B 细胞和肥大细胞相关通路，从而对免疫球蛋白 E (IgE) 的产生和 AED 表现起关键作用。因此，可以通过淋巴管Vegfr3的遗传抑制来缓解眼部过敏。有趣的是，促淋巴管生成的 VEGFR3 信号似乎不影响睑板腺 (MG) 的阻塞或与 AED 相关的 Th17 型和中性粒细胞通路的激活。

结论

这些数据揭示了促淋巴管生成性 VEGFR3 信号在 AED 发展中的关键作用，并提供了实验证据表明 VEGFR3 抑制可能有助于治疗患者的眼部过敏。