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Role of NF-kappaB-dependent proinflammatory mast cell functions in immune responses

NF-κB依赖性促炎肥大细胞功能在免疫反应中的作用

基本信息

批准号：
214654394
负责人：
Professor Dr. Axel Roers
金额：
--
依托单位：
Institut für Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/214654394?language=en
关键词：
Role NF kappaB dependent proinflammatory

项目摘要

Crosslinking of mast cell surface IgE results in rapid release of preformed vasoactive and proinflammatory mediators and, several hours later, additional de novo production of pro-inflammatory mediators. Both these phases are central to the pathogenesis of allergic disease. Numerous other pathways can trigger mast cell activation. In particular, mast cells express pattern recognition receptors suggesting roles in pathogen defense. Functions of mast cells in immune responses were described in kit mutant mouse models of mast cell-deficiency. We have shown, however, that experiments in these mice, can be misleading and have therefore generated novel Cre/loxP-based models for the investigation of mast cell biology. In order to clarify the relevance of pro-inflammatory mast cell functions in immune responses, we created mice with mast cell-specific inactivation or hyperactivation of the pro-inflammatory NF-κB signaling pathway. This was achieved by conditional knock out of the genes encoding IKK2 or NEMO in mast cells, or by mast cell-specific expression of a mutant IKK2 protein, respectively. The present grant aims to characterize these mouse lines for alterations of immune responses, including IgE-mediated responses. Our first results indicate that mast cell NF-κB signaling is essential for T cell and late phase mast cell responses. Contradicting published literature, our data suggest that IKK2 is dispensable for mast cell degranulation.

肥大细胞表面IgE的交联导致预先形成的血管活性和促炎介质的快速释放，并且几小时后，促炎介质的额外从头产生。这两个阶段都是过敏性疾病发病机制的核心。许多其他途径可以触发肥大细胞活化。特别是，肥大细胞表达模式识别受体，提示在病原体防御中的作用。在肥大细胞缺陷的kit突变小鼠模型中描述了肥大细胞在免疫应答中的功能。然而，我们已经表明，在这些小鼠中进行的实验可能会产生误导，因此产生了新的基于Cre/loxP的模型，用于肥大细胞生物学的研究。为了阐明促炎性肥大细胞功能在免疫应答中的相关性，我们建立了促炎性NF-κB信号通路肥大细胞特异性失活或过度活化的小鼠。这是通过条件性敲除肥大细胞中编码IKK 2或NEMO的基因，或通过突变IKK 2蛋白的肥大细胞特异性表达来实现的。目前的资助旨在表征这些小鼠系的免疫反应的改变，包括IgE介导的反应。我们的第一个结果表明，肥大细胞NF-κB信号是必不可少的T细胞和晚期肥大细胞的反应。与已发表的文献相矛盾，我们的数据表明IKK 2与肥大细胞脱颗粒有关。