The lymphatic system plays an active role during infection, however the role of lymphatic-neutrophil interactions in host-defense responses is not well understood. During infection with pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus and Yersinia pestis, neutrophils traffic from sites of infection through the lymphatic vasculature, to draining lymph nodes to interact with resident lymphocytes. This process is poorly understood, in part, due to the lack of in vitro models of the lymphatic system. Here we use a 3D microscale lymphatic vessel model to examine neutrophil-lymphatic cell interactions during host defense responses to pathogens. In previous work, we have shown that follistatin is secreted at high concentrations by lymphatic endothelial cells during inflammation. Follistatin inhibits activin A, a member of the TGF-β superfamily, and, together, these molecules form a signaling pathway that plays a role in regulating both innate and adaptive immune responses. Although follistatin and activin A are constitutively produced in the pituitary, gonads and skin, their major source in the serum and their effects on neutrophils are poorly understood. Here we report a microfluidic model that includes both blood and lymphatic endothelial vessels, and neutrophils to investigate neutrophil-lymphatic trafficking during infection with P. aeruginosa. We found that lymphatic endothelial cells produce secreted factors that increase neutrophil migration toward P. aeruginosa, and are a significant source of both follistatin and activin A during Pseudomonas infection. We determined that follistatin produced by lymphatic endothelial cells inhibits activin A, resulting in increased neutrophil migration. These data suggest that the follistatin:activin A ratio influences neutrophil trafficking during infection with higher ratios increasing neutrophil migration.

中文翻译：

---

淋巴管内皮衍生的卵泡抑素：激活素 A 轴调节中性粒细胞运动以响应铜绿假单胞菌。


淋巴系统在感染过程中发挥着积极作用，然而淋巴管-中性粒细胞相互作用在宿主防御反应中的作用尚不清楚。在感染铜绿假单胞菌、金黄色葡萄球菌和鼠疫耶尔森氏菌等病原体时，中性粒细胞从感染部位通过淋巴管系统到达引流淋巴结，与驻留淋巴细胞相互作用。人们对这一过程知之甚少，部分原因是缺乏淋巴系统的体外模型。在这里，我们使用 3D 微型淋巴管模型来检查宿主对病原体的防御反应期间中性粒细胞 - 淋巴细胞的相互作用。在之前的工作中，我们已经证明，炎症期间淋巴内皮细胞会高浓度地分泌卵泡抑素。卵泡抑素抑制激活素 A（TGF-β 超家族的成员），并且这些分子一起形成信号通路，在调节先天性和适应性免疫反应中发挥作用。尽管卵泡抑素和激活素 A 在垂体、性腺和皮肤中组成型产生，但它们在血清中的主要来源及其对中性粒细胞的影响却知之甚少。在这里，我们报告了一种微流体模型，其中包括血液和淋巴内皮血管以及中性粒细胞，用于研究铜绿假单胞菌感染期间中性粒细胞-淋巴运输。我们发现淋巴内皮细胞产生分泌因子，增加中性粒细胞向铜绿假单胞菌的迁移，并且是假单胞菌感染期间卵泡抑素和激活素 A 的重要来源。我们确定淋巴内皮细胞产生的卵泡抑素会抑制激活素 A，从而导致中性粒细胞迁移增加。 这些数据表明，卵泡抑素：激活素 A 的比率影响感染期间的中性粒细胞运输，较高的比率会增加中性粒细胞的迁移。