The function of factor X and PAR-2 in the early immune response against Leishmania major

X因子和PAR-2在针对重大利什曼原虫的早期免疫反应中的作用

• 批准号: 328105851
• 负责人: Privatdozent Dr. Jan Ehrchen
• 金额: --
• 依托单位: Universitätsklinik und Poliklinik für Dermatologie und Venerologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/328105851?language=en
• 关键词: function; factor; PAR; early; immune

The Infection of susceptible and resistant mice strains with Leishmania major is a model disease for natural resistance and the development of Th2- or Th1-cells.Our focus lies on the events at the site of infection. We pursue the hypothesis that Th-cell differentiation in the lymph node is crucially influenced by signals from the early, tightly regulated inflammatory micromilieu in the infected skin. So called danger signals produced in the infected skin influence the function of antigen presenting cells prior to their migration to the lymph node and the subsequent interaction with T-cells in the lymph node via third signals.Using a genome wide characterization, we found several local tissue signals which are early and differentially expressed between susceptible and resistant mice. Remarkably, the expression of several known Th1-inducing cytokines was temporally restricted to the first two days of infection, coinciding with the time frame during which the T-cell response is determined. One important source are keratinocytes. Due of their high number, they are able to produce sufficient amounts of cytokines. One of the few genes more highly expressed in susceptible mice is the chemokine CXCL11. It causes a Th2 response and higher parasite titers when injected in resistant C57BL/6 mice, but its local neutralization did not cause a Th1 response in BALB/c mice.Therefore we have focused again on potential Th1-inducing signals. We had previously focused on genes already implied in Th1 differentiation. We now have widened our scope as we had also found higher expression of coagulation factor X (FX) in the skin of resistant C57BL/6 mice. In mice of resistant background which are deficient for a known receptor of FX, i.e. protease-activated receptor 2 (PAR-2), we then observed higher parasite titers and a Th2 response. Since the coagulatory and immune systems influence each other and because PAR-2 and FX probably play a key role in this, we now want to further investigate these findings.Thus, the goal of this project is to unravel the mechanisms by which PAR-2 contributes to resistance and the relevance of FX and other PAR-2 agonists in this process. Moreover, we want to establish whether other factors of the coagulation system are involved in the Th1/Th2 immune response and whether the coagulation system is a pharmacological target in leishmaniasis and other infections.We expect further insights in both the pathophysiology of leishmaniasis as well as in general mechanisms of Th-cell differentiation, all in context of the interdependence of the coagulatory system and inflammation. The results may facilitate new therapeutic approaches in other Th1- or Th2-dependent inflammations.

大利什曼原虫易感和耐药小鼠株的感染是自然抵抗和Th2或Th1细胞发展的模式疾病。我们的重点是感染部位的事件。我们坚持这样一种假设，即淋巴结中的Th细胞分化受到感染皮肤中早期严格调控的炎症微环境信号的关键影响。在感染的皮肤中产生的所谓的危险信号在抗原提呈细胞迁移到淋巴结之前影响它们的功能，并随后通过第三信号与淋巴结中的T细胞相互作用。利用全基因组特征，我们发现了几个在敏感和耐药小鼠之间早期和差异表达的局部组织信号。值得注意的是，几种已知的Th1诱导细胞因子的表达被暂时限制在感染的头两天，这与确定T细胞反应的时间框架一致。角质形成细胞是一个重要的来源。由于它们的数量很多，它们能够产生足够数量的细胞因子。在易感小鼠中，少数几个高表达的基因之一是趋化因子CXCL11。当注射到耐药的C57BL/6小鼠中时，它会引起Th2反应和更高的寄生虫滴度，但它的局部中和不会在BALB/c小鼠中引起Th1反应。因此，我们再次关注潜在的Th1诱导信号。我们之前关注的是已经隐含在Th1分化中的基因。我们现在扩大了我们的范围，因为我们还发现抗药性C57BL/6小鼠皮肤中凝血因子X(FX)的表达增加。在缺乏已知FX受体，即蛋白酶激活受体2(PAR-2)的抗性背景的小鼠中，我们观察到较高的寄生虫滴度和Th2反应。由于凝血和免疫系统相互影响，而且PAR-2和FX可能在其中起关键作用，我们现在希望进一步研究这些发现。因此，本项目的目标是揭示PAR-2促进耐药性的机制以及FX和其他PAR-2激动剂在这一过程中的相关性。此外，我们希望确定凝血系统的其他因素是否参与Th1/Th2免疫反应，以及凝血系统是否是利什曼病和其他感染的药理靶点。我们希望在利什曼病的病理生理学和Th细胞分化的一般机制方面有进一步的深入了解，所有这些都是在凝血系统和炎症相互依赖的背景下。这一结果可能为其他Th1或Th2依赖型炎症提供新的治疗方法。