The role of lymph flow in regulation of innate immunity

淋巴液流动在调节先天免疫中的作用

• 批准号: RGPIN-2022-03558
• 负责人: Liao, Shan
• 金额: $ 2.04万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761056
• 关键词: role; lymph; flow; regulation; innate

After an immune stimulation, lymphatic vessels transport antigens, regulatory factors, and cells to the lymph node (LN) to initiate protective immunity. Immune responses in the LN (innate and adaptive immunity) take place in a timely manner, and each step depends on some degree of functional lymphatic vessels. However, the role of lymph in immune regulation is often ignored and thus is poorly understood. The lymph composition rapidly changes after an immune stimulation. Using Staphylococcus aureus (S. aureus) skin infection as an immune stimulation model, we will study how lymph regulates neutrophil migration as an early step of host immune defense in the LN. The long-term goal of our study is to elucidate how lymph regulates innate immune protection in the LN. Afferent lymphatic vessels transport lymph to the LN in a matter of minutes allowing changes in the infected area to reach the LN timely. In the LN, lymph flows along a specialized network called conduits to deliver small molecular weight antigens and regulatory factors to their designated locations in the LN parenchyma efficiently. After immune surveillance, lymph and cells exit the LN via efferent lymphatic vessels. The movement of lymph and cells is finely tuned for optimal immune responses in the LNs. After S. aureus skin infection, neutrophils are the first large population of circulating leukocytes to rapidly infiltrate the infected skin and the draining LN to eliminate the bacteria and prevent their systemic spread. In the first 4 hours post-infection (4hpi), neutrophils predominantly infiltrate the LN from high endothelial venules (HEVs). HEVs are specialized LN blood vessels that allow immune cell homing to the LN in homeostatic status. However, neutrophils rarely enter the LN in homeostasis. How can HEVs in the LN react to skin infection in such a short time frame? In preliminary studies, we have found that blocking afferent lymphatic vessels inhibited neutrophil migration in the LN, but not in the skin area infected by S. aureus. Without lymph flow, bacteria in the LN could not effectively recruit neutrophils. Alternatively, neutrophil migration chemokines, CXCL1 and CXCL2, in the skin were sufficient to recruit neutrophils in the LN. We hypothesize that in the early stage of infection, lymphatic vessels transport bacteria and immune regulatory factors in lymph to the LN, and conduits relay lymph-borne immune regulatory factors to HEVs to direct neutrophil migration. Impaired lymph flow interrupts neutrophil migration in the LN. To test this hypothesis, we will dissect how blocking afferent lymphatic vessels (Aim 1); blocking efferent lymphatic vessels (Aim 2) and changing lymph flow along the conduits (Aim 3) regulate neutrophil migration in the LN. Our research program will reveal fundamental mechanism of how lymph participates in immune regulation in the LN.

免疫刺激后，淋巴管将抗原、调节因子和细胞转运至淋巴结 (LN) 以启动保护性免疫。 LN 中的免疫反应（先天性免疫和适应性免疫）及时发生，每个步骤都取决于某种程度的功能性淋巴管。然而，淋巴在免疫调节中的作用经常被忽视，因此人们对其知之甚少。免疫刺激后，淋巴成分会迅速发生变化。使用金黄色葡萄球菌（S. aureus）皮肤感染作为免疫刺激模型，我们将研究淋巴如何调节中性粒细胞迁移，作为淋巴结中宿主免疫防御的早期步骤。我们研究的长期目标是阐明淋巴如何调节淋巴结中的先天免疫保护。传入淋巴管在几分钟内将淋巴液输送至淋巴结，使感染区域的变化及时到达淋巴结。在淋巴结中，淋巴液沿着称为导管的专门网络流动，将小分子量抗原和调节因子有效地输送到淋巴结实质中的指定位置。免疫监视后，淋巴液和细胞通过传出淋巴管离开淋巴结。淋巴液和细胞的运动经过精心调整，以实现淋巴结中的最佳免疫反应。金黄色葡萄球菌皮肤感染后，中性粒细胞是第一批大量的循环白细胞，可迅速渗透到受感染的皮肤和引流淋巴结，以消除细菌并防止其全身扩散。在感染后的前 4 小时 (4hpi)，中性粒细胞主要从高内皮微静脉 (HEV) 渗入淋巴结。 HEV 是特殊的 LN 血管，允许免疫细胞在稳态状态下归巢到 LN。然而，中性粒细胞很少进入体内平衡的淋巴结。 LN 中的 HEV 如何在如此短的时间内对皮肤感染做出反应？ 在初步研究中，我们发现阻断传入淋巴管可抑制中性粒细胞在淋巴结中的迁移，但不会抑制金黄色葡萄球菌感染的皮肤区域的中性粒细胞迁移。如果没有淋巴流动，淋巴结中的细菌就无法有效地募集中性粒细胞。或者，皮肤中的中性粒细胞迁移趋化因子 CXCL1 和 CXCL2 足以招募 LN 中的中性粒细胞。我们推测，在感染早期，淋巴管将淋巴液中的细菌和免疫调节因子转运至淋巴结，并将淋巴液中的免疫调节因子传​​递给HEV，从而引导中性粒细胞迁移。淋巴液流动受损会中断中性粒细胞在淋巴结中的迁移。为了检验这个假设，我们将剖析如何阻塞传入淋巴管（目标 1）；阻断传出淋巴管（目标 2）并改变淋巴管沿导管的流动（目标 3）调节中性粒细胞在淋巴结中的迁移。我们的研究计划将揭示淋巴如何参与淋巴结免疫调节的基本机制。