iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice.
iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice.
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DOI：
10.1371/journal.ppat.1000494
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发表时间：
2009-06
期刊：
影响因子：
6.7
通讯作者：
Muraille E
中科院分区：
文献类型：
--
作者：
De Trez C;Magez S;Akira S;Ryffel B;Carlier Y;Muraille E
利什曼原虫主要寄生并繁殖于宿主吞噬细胞的内体晚期。利什曼原虫生长的免疫控制绝对需要诱导型一氧化氮合酶（iNOS/NOS2）的表达和随后NO的产生。在这里，我们发现CD11b+ CD11c+ Ly-6C+ MHC-II+细胞是利什曼原虫感染的C57BL/6小鼠脚垫病变和引流淋巴结中主要的inos产生细胞。这些细胞在表型上与单核增生李斯特菌和梅利氏菌感染小鼠模型中观察到的产生inos的炎性DC （iNOS-DC）相似。使用表达dsred的寄生虫表明，这些产生inos的细胞是病变和引流淋巴结的主要感染群体。对多种基因缺陷小鼠品系的分析显示，在引流淋巴结募集iNOS-DC需要CCR2的表达，而它们的激活强烈依赖于CD40、IL-12、IFN-γ和MyD88分子，TNF-α和TLR9也有部分贡献。相反，STAT-6缺乏增强了易感BALB/c小鼠中iNOS-DC的募集和激活，表明IL-4和IL-13是负调控因子的关键作用。综上所述，我们的研究结果表明iNOS-DC代表了th1调控的效应细胞群的一个主要类别，并且构成了C57BL/6耐药小鼠慢性利什曼原虫主要感染期最常见的感染细胞类型。利什曼原虫是一种原生动物寄生虫，感染多种哺乳动物，包括人类和老鼠。从利什曼原虫大感染的小鼠模型中收集了许多信息。耐药C57BL/6小鼠对L. major感染的控制需要T细胞分泌1型（Th1）细胞因子（即IFN-γ）和吞噬细胞表达诱导型一氧化氮合酶（iNOS）。相反，易感BALB/c小鼠无法控制感染，并产生以分泌IL-4和IL-13细胞因子为特征的2型（Th2）免疫应答。在这项研究中，我们发现病变和引流淋巴结中的主要inos产生细胞在表型上类似于产生inos的“炎性”树突状细胞（DC），这已经在单核增生李斯特菌和布鲁氏菌感染的小鼠模型中被描述。我们的数据还强调了这些炎性DC的募集和激活与对L. major感染的抵抗力之间的强烈关联。此外，我们发现这些炎性DC产生的iNOS受Th1反应的正调控，而受Th2反应的负调控。综上所述，我们的结果为先天和适应性免疫反应如何对抗L. major感染提供了新的见解。更好地了解调节炎症DC募集和激活的机制可能会导致对抗利什曼原虫感染的新治疗策略。
Leishmania major parasites reside and multiply in late endosomal compartments of host phagocytic cells. Immune control of Leishmania growth absolutely requires expression of inducible Nitric Oxide Synthase (iNOS/NOS2) and subsequent production of NO. Here, we show that CD11b+ CD11c+ Ly-6C+ MHC-II+ cells are the main iNOS-producing cells in the footpad lesion and in the draining lymph node of Leishmania major-infected C57BL/6 mice. These cells are phenotypically similar to iNOS-producing inflammatory DC (iNOS-DC) observed in the mouse models of Listeria monocytogenes and Brucella melitensis infection. The use of DsRed-expressing parasites demonstrated that these iNOS-producing cells are the major infected population in the lesions and the draining lymph nodes. Analysis of various genetically deficient mouse strains revealed the requirement of CCR2 expression for the recruitment of iNOS-DC in the draining lymph nodes, whereas their activation is strongly dependent on CD40, IL-12, IFN-γ and MyD88 molecules with a partial contribution of TNF-α and TLR9. In contrast, STAT-6 deficiency enhanced iNOS-DC recruitment and activation in susceptible BALB/c mice, demonstrating a key role for IL-4 and IL-13 as negative regulators. Taken together, our results suggest that iNOS-DC represent a major class of Th1-regulated effector cell population and constitute the most frequent infected cell type during chronic Leishmania major infection phase of C57BL/6 resistant mice. Leishmania spp. are protozoan parasites infecting a variety of mammals, including humans and mice. Much information has been gleaned from murine models of Leishmania major infection. The control of L. major infection by resistant C57BL/6 mice requires the secretion of type 1 (Th1) cytokines (i.e. IFN-γ) by T cells as well as the expression of inducible nitric oxide synthase (iNOS) by phagocytic cells. Conversely, susceptible BALB/c mice are unable to control infection and develop a type 2 (Th2) immune response characterized by the secretion of IL-4 and IL-13 cytokines. In this study, we showed that the main iNOS-producing cells in the lesion and the draining lymph node are phenotypically similar to iNOS-producing “inflammatory” dendritic cells (DC), which are already described in the mouse models of Listeria monocytogenes and Brucella melitensis infection. Our data also highlighted a strong association between the recruitment and activation of these inflammatory DC and the resistance to L. major infection. In addition, we showed that iNOS production by these inflammatory DC is positively regulated by Th1 response and negatively by Th2 response. Taken together, our results provide new insights into how innate and adaptive immune responses fight L. major infection. A better understanding of the mechanisms regulating inflammatory DC recruitment and activation could lead to new therapeutic strategies against Leishmania infection.
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