Dectin-1 Signaling Mechanisms

总结/摘要 Dectin-1是由骨髓吞噬细胞如巨噬细胞和树突状细胞表达的先天性免疫受体， 这些细胞对于宿主有效防御真菌感染至关重要。Dectin-1识别β-1，3-葡聚糖 多糖，占真菌细胞壁干重的一半，以及受体的激活 引发吞噬作用，产生杀微生物活性氧，并产生大量的亲- 炎性细胞因子Dectin-1是迄今为止仅有的几种足以触发 因此，它已成为了解这种受体如何工作的重要模型。这 更新项目的重点是进一步了解Dectin-1信号传导的机制。先前的研究 记录了Dectin-1信号对常见酵母如白色念珠菌的应答促进IL-23 树突状细胞的产生，与其他炎症介质一起，支持良好的Th 1/Th 17 T细胞 反应这种反应对于真菌感染的粘膜免疫是必不可少的。相反，我们现在观察到， C.白念珠菌菌丝激活树突状细胞，以驱动更好地表征为Th 2/Th 9的应答，而Dectin- 1对于这种反应也至关重要。此外，我们注意到，某些真菌，包括念珠菌属的殖民。 和瓦氏菌属（Wallemia spp.）加剧Th 2/9驱动的过敏性气道疾病小鼠模型。在这个项目中，我们将 研究Dectin-1信号通路促进Th 2和Th 9型免疫的机制 体外和体内反应。我们将进一步开发新的策略， 信号通路

SUMMARY/ABSTRACT Dectin-1 is an innate immune receptor expressed by myeloid phagocytes such as macrophages and dendritic cells that is essential for effective host defense against fungal infections. Dectin-1 recognizes the β-1,3-glucan polysaccharide that makes up as much as half the dry weight of fungal cell walls, and activation of the receptor triggers phagocytosis, production of microbicidal reactive oxygen species, and production of a host of pro- inflammatory cytokines. Dectin-1 is one of only a few receptors so far shown to be sufficient for triggering phagocytosis, and it has thus become an important model for understanding how such receptors work. This renewal project focuses on further understanding the mechanisms of Dectin-1 signaling. Previous studies have documented that Dectin-1 signaling in response to common yeast such as Candida albicans promotes IL-23 production by dendritic cells that, together with other inflammatory mediators, supports a good Th1/Th17 T cell response. This response is essential for mucosal immunity to fungal infections. In contrast, we now observe that C. albicans hyphae activate dendritic cells to drive a response better characterized as Th2/Th9 and that Dectin- 1 is also critical for this response. Further, we note that colonization with certain fungi including Candida spp. and Wallemia spp. exacerbate Th2/9-driven mouse models of allergic airway disease. In this project, we will investigate the mechanisms by which the Dectin-1 signaling pathway promotes Th2 and Th9 type immune responses in vitro and in vivo. We will further develop novel strategies for pharmacologically manipulating this signaling pathway.