Duarte Nádia, Shafi Abdul Muktadir, Penha-Gonçalves Carlos, Pais Teresa Faria
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Front Cell Dev Biol. 2023 Sep 14;11:1249235. doi: 10.3389/fcell.2023.1249235. eCollection 2023.
The endothelium layer lining the inner surface of blood vessels serves relevant physiological functions in all body systems, including the exchanges between blood and extravascular space. However, endothelial cells also participate in innate and adaptive immune response that contribute to the pathophysiology of inflammatory disorders. Type I Interferon (IFN) signaling is an inflammatory response triggered by a variety of pathogens, but it can also be induced by misplaced DNA in the cytosol caused by cell stress or gene mutations. Type I IFN produced by blood leukocytes or by the endothelium itself is well-known to activate the interferon receptor (IFNAR) in endothelial cells. Here, we discuss the induction of type I IFN secretion and signaling in the endothelium, specifically in the brain microvasculature where endothelial cells participate in the tight blood-brain barrier (BBB). This barrier is targeted during neuroinflammatory disorders such as infection, multiple sclerosis, Alzheimer's disease and traumatic brain injury. We focus on type I IFN induction through the cGAS-STING activation pathway in endothelial cells in context of autoinflammatory type I interferonopathies, inflammation and infection. By comparing the pathophysiology of two separate infectious diseases-cerebral malaria induced by infection and COVID-19 caused by SARS-CoV-2 infection-we emphasize the relevance of type I IFN and STING-induced vasculopathy in organ dysfunction. Investigating the role of endothelial cells as active type I IFN producers and responders in disease pathogenesis could lead to new therapeutic targets. Namely, endothelial dysfunction and brain inflammation may be avoided with strategies that target excessive STING activation in endothelial cells.
血管内表面的内皮细胞层在所有身体系统中发挥着相关的生理功能，包括血液与血管外空间之间的物质交换。然而，内皮细胞也参与先天性和适应性免疫反应，这些反应会导致炎症性疾病的病理生理过程。I型干扰素（IFN）信号传导是由多种病原体触发的炎症反应，但它也可能由细胞应激或基因突变导致的胞质溶胶中错位的DNA所诱导。众所周知，血液白细胞或内皮细胞自身产生的I型干扰素会激活内皮细胞中的干扰素受体（IFNAR）。在此，我们讨论内皮细胞中I型干扰素分泌和信号传导的诱导过程，特别是在脑微血管中，内皮细胞参与构成紧密的血脑屏障（BBB）。在诸如感染、多发性硬化症、阿尔茨海默病和创伤性脑损伤等神经炎症性疾病中，这个屏障会成为攻击目标。我们关注在自身炎症性I型干扰素病、炎症和感染的背景下，通过内皮细胞中的cGAS-STING激活途径诱导I型干扰素的过程。通过比较两种不同传染病的病理生理学——由感染引起的脑型疟疾和由SARS-CoV-2感染导致的COVID-19——我们强调I型干扰素和STING诱导的血管病变在器官功能障碍中的相关性。研究内皮细胞作为疾病发病机制中I型干扰素的活跃生产者和反应者的作用，可能会带来新的治疗靶点。具体而言，通过针对内皮细胞中过度的STING激活的策略，或许可以避免内皮功能障碍和脑部炎症。
