IL-23 (Interleukin-23)-Producing Conventional Dendritic Cells Control the Detrimental IL-17 (Interleukin-17) Response in Stroke
IL-23 (Interleukin-23)-Producing Conventional Dendritic Cells Control the Detrimental IL-17 (Interleukin-17) Response in Stroke
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DOI：
10.1161/strokeaha.117.019101
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发表时间：
2018-01-01
期刊：
影响因子：
8.3
通讯作者：
Magnus, Tim
中科院分区：
文献类型：
--
作者：
Gelderblom, Mathias;Gallizioli, Mattia;Magnus, Tim
背景和目的：炎症机制可加重缺血性组织损伤，并使卒中患者的临床结局恶化。α-β和γ-δ T细胞都是中风中组织损伤的既定介质，树突状细胞（DC）在诱导中风中T细胞活化和分化的早期事件中的作用尚不清楚。方法在实验性中风的小鼠模型中，我们基于表面标志物的流式细胞术、个体发生标志物的表达、和细胞因子水平。我们使用条件性DC耗竭、骨髓嵌合小鼠和IL-23（白细胞介素-23）受体缺陷小鼠进一步探索DCs.Results-We显示缺血性脑被IRF 4（+）/CD 172 a（+）常规2型DC快速浸润，并且与所有其他DC亚群相比，常规2型DC是最丰富的亚群。缺血发作后24小时，常规2型DC成为IL-23的主要来源，通过诱导γ δ T细胞中的IL-17（白细胞介素-17）促进中性粒细胞浸润。在功能上，CD 11 c（+）细胞的耗竭或IL-23信号传导的遗传破坏消除了γ δ T细胞中的IL-17产生和中性粒细胞浸润。中断的IL-23/ IL-17级联减少梗死面积和改善神经功能的结果后stroke. Conclusions，我们的研究结果表明，干扰素调节因子4阳性IL-23产生的传统的DC在IL-17依赖的继发性组织损伤中风的核心作用。
Background and Purpose-Inflammatory mechanisms can exacerbate ischemic tissue damage and worsen clinical outcome in patients with stroke. Both alpha beta and gamma delta T cells are established mediators of tissue damage in stroke, and the role of dendritic cells (DCs) in inducing the early events of T cell activation and differentiation in stroke is not well understood.Methods-In a murine model of experimental stroke, we defined the immune phenotype of infiltrating DC subsets based on flow cytometry of surface markers, the expression of ontogenetic markers, and cytokine levels. We used conditional DC depletion, bone marrow chimeric mice, and IL-23 (interleukin-23) receptor-deficient mice to further explore the functional role of DCs.Results-We show that the ischemic brain was rapidly infiltrated by IRF4(+)/ CD172a(+) conventional type 2 DCs and that conventional type 2 DCs were the most abundant subset in comparison with all other DC subsets. Twenty-four hours after ischemia onset, conventional type 2 DCs became the major source of IL-23, promoting neutrophil infiltration by induction of IL-17 (interleukin-17) in gamma delta T cells. Functionally, the depletion of CD11c(+) cells or the genetic disruption of the IL-23 signaling abrogated both IL-17 production in gamma delta T cells and neutrophil infiltration. Interruption of the IL-23/ IL-17 cascade decreased infarct size and improved neurological outcome after stroke.Conclusions-Our results suggest a central role for interferon regulatory factor 4-positive IL-23-producing conventional DCs in the IL-17-dependent secondary tissue damage in stroke.