Keratinocytes determine Th1 immunity during early experimental leishmaniasis.
Keratinocytes determine Th1 immunity during early experimental leishmaniasis.
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DOI：
10.1371/journal.ppat.1000871
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发表时间：
2010-04-29
期刊：
影响因子：
6.7
通讯作者：
Sunderkötter C
中科院分区：
文献类型：
--
作者：
Ehrchen JM;Roebrock K;Foell D;Nippe N;von Stebut E;Weiss JM;Münck NA;Viemann D;Varga G;Müller-Tidow C;Schuberth HJ;Roth J;Sunderkötter C
实验性利什曼病是分析Th 1/Th 2分化的良好模型系统。抗利什曼原虫（L.）主要取决于L的发展。主要特异性Th 1应答，而Th 2分化导致易感性。越来越多的证据表明，早期受影响组织的微环境提供了Th细胞分化的初始触发因素。为了分析这一点，我们研究了寄生虫接种后16小时抵抗和易感小鼠感染皮肤中的差异基因表达。运用微阵列技术、生物信息学、激光显微切割和原位杂交技术，我们发现表皮是免疫调节介质的主要来源。这种表皮基因诱导在抗性小鼠中显著更强，特别是对于已知促进Th 1分化的几种基因（IL-12、IL-1β、骨桥蛋白、IL-4）和IL-6。这些细胞因子的表达暂时限制在Th 1/2分化的关键时刻。此外，我们揭示了一个更强的表皮上调IL-6在耐药小鼠的表皮。因此，在抗性小鼠中IL-4的早期局部中和导致Th 2转换，并且在非造血细胞中具有选择性IL-6缺陷的小鼠显示Th 2转换和疾病的显著恶化。因此，我们的数据首次表明，表皮细胞因子的表达是一个决定性的因素，在保护性Th 1免疫的产生，并有助于感染这种重要的人类病原体的结果。为了清除寄生虫利什曼原虫的皮肤感染，必须产生特异性T辅助（Th）细胞免疫应答。Th细胞应答的类型在感染后早期由尚不清楚的机制确定。在抗性小鼠中产生Th 1模式。然而，BALB/c小鼠中的Th 2模式导致易感性。分析这些机制对于更好地理解宿主-寄生虫相互作用和非感染性Th细胞驱动的炎性皮肤病（例如特应性皮炎）是重要的。我们分析了受感染的皮肤如何影响Th细胞反应。因此，我们比较了耐药和易感小鼠皮肤感染后早期的基因表达。几种细胞因子（如IL-1β、IL-12、骨桥蛋白、IL-4和IL-6）在抗性小鼠的皮肤中更强烈地产生，因此对于Th 1分化可能是重要的。我们证明，他们表达的表皮角质形成细胞。使用在角质形成细胞中而不是在免疫细胞中缺乏IL-6的小鼠，并通过抑制早期产生的IL-4的作用，我们揭示了角质形成细胞衍生的IL-6和IL-4对于抵抗利什曼原虫是重要的。因此，我们的研究结果表明，表皮控制Th 1分化，并可能是一个新的药理学目标的修改Th分化。
Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediators. This epidermal gene induction was significantly stronger in resistant mice especially for several genes known to promote Th1 differentiation (IL-12, IL-1β, osteopontin, IL-4) and for IL-6. Expression of these cytokines was temporally restricted to the crucial time of Th1/2 differentiation. Moreover, we revealed a stronger epidermal up-regulation of IL-6 in the epidermis of resistant mice. Accordingly, early local neutralization of IL-4 in resistant mice resulted in a Th2 switch and mice with a selective IL-6 deficiency in non-hematopoietic cells showed a Th2 switch and dramatic deterioration of disease. Thus, our data indicate for the first time that epidermal cytokine expression is a decisive factor in the generation of protective Th1 immunity and contributes to the outcome of infection with this important human pathogen. To clear skin infections with the parasite Leishmania major, a specific T-helper (Th)-cell immune response has to be generated. The type of Th-cell response is determined early after infection by yet unknown mechanisms. In resistant mice a Th1-pattern is generated. A Th2-pattern in BALB/c mice, however, results in susceptibility. An analysis of these mechanisms is important for a better understanding of both host-parasite interactions and non-infectious Th-cell driven inflammatory skin disorders (e.g. atopic dermatitis). We analyzed how the infected skin influenced the Th-cell response. Therefore, we compared gene-expression early after infection in the skin of resistant and susceptible mice. Several cytokines (like IL-1β, IL-12, osteopontin, IL-4 and IL-6) were more strongly produced in the skin of resistant mice and therefore could be important for Th1-differentiation. We demonstrated that they were expressed by epidermal keratinocytes. Using mice with a deficiency for IL-6 in keratinocytes but not in immune cells and by inhibiting the action of early produced IL-4 we revealed that keratinocyte-derived IL-6 and IL-4 are important for resistance against Leishmania. Thus, our results indicate that the epidermis controls Th1-differentiation and may be a new pharmacological target for modification of Th-differentiation.
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影响因子：
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