Non-Toll-like receptor innate immune signaling

描述（由申请人提供）：先天免疫受体触发炎症，激活微生物杀伤机制，并指导获得性免疫应答的发展。先天免疫识别受体的Toll样受体（TLR）家族是目前描述最完整的先天受体家族。这些受体在识别广泛的微生物产物、触发NF-β B活化和产生大量细胞因子和趋化因子方面起关键作用，并且已被证明是有效抵抗许多病原体的宿主防御所必需的。然而，TLR并不激活所有的先天宿主防御，并且另外的“非TLR”先天免疫受体触发吞噬作用，激活抗微生物杀伤机制，塑造TLR信号传导的结果，并且可能对于有效的宿主防御同样重要。目前，这些非TLR先天受体中很少有被定义。我们已经建立了葡聚糖受体Dectin-1作为一种基于非TLR的先天免疫识别模型。该受体触发含葡聚糖颗粒（如酵母）的吞噬作用，并激活抗微生物活性氧物质的产生。Dectin-1信号传导还与TLR信号传导协作以协调细胞细胞因子和趋化因子的产生。虽然TLR信号传导相对较好地理解并且与细胞因子受体信号传导有许多共同之处，但是我们已经发现Dectin-1信号传导与抗原受体信号传导有许多共同之处。因此，通常与获得性免疫相关的信号传导途径，包括Src/Syk和NFAT（活化T细胞的核因子）途径，在暴露于酵母聚糖或酵母时在吞噬细胞中被活化。我们将检验NFAT的先天免疫激活是炎症反应的重要组成部分这一假设。 目的1将定义Dectin-1和酵母激活巨噬细胞、树突状细胞和中性粒细胞中Src家族激酶和Syk的机制。在目标2中，我们将探索Dectin-1激活NFAT的机制以及NFAT激活对体外炎症反应的影响。在目标3中，我们将定义Dectin-1和NFAT信号传导在体内先天性和适应性免疫应答中的作用的效果。

DESCRIPTION (provided by applicant): Innate immune receptors trigger inflammation, activate microbial killing mechanisms, and instruct the development of acquired immune responses. The Toll-like receptor (TLR) family of innate immune recognition receptors is currently the most completely described family of innate receptors. These receptors play crucial roles in recognizing a wide range of microbial products, trigger NF-(B activation and production of a host of cytokines and chemokines, and have been demonstrated to be essential for effective host defense against many pathogens. However, TLRs do not activate all innate host defenses, and additional "non-TLR" innate immune receptors trigger phagocytosis, activate antimicrobial killing mechanisms, shape the consequences of TLR signaling, and are likely equally essential for effective host defense. Currently very few of these non-TLR innate receptors have been defined. We have established the ¿-glucan receptor Dectin-1 as one model for non-TLR based innate immune recognition. This receptor triggers phagocytosis of ¿-glucan-containing particles (such as yeast) and activates production of antimicrobial reactive oxygen species. Dectin-1 signaling also collaborates with TLR signaling to orchestrate cellular cytokine and chemokine production. While TLR signaling is relatively well-understood and shares much in common with cytokine receptor signaling, we have discovered that Dectin-1 signaling shares much in common with antigen receptor signaling. Thus signaling pathways generally associated with acquired immunity including the Src/Syk and NFAT (Nuclear Factor of Activated T cells) pathways are activated in phagocytes upon exposure to zymosan or yeast. We will examine the hypothesis that innate immune activation of NFAT is an important component of inflammatory responses. In Aim 1 will define the mechanisms by which Dectin-1 and yeast activate Src family kinases and Syk in macrophages, dendritic cells, and neutrophils. In Aim 2 we will explore the mechanisms by which Dectin-1 activates NFAT and the consequences of NFAT activation on inflammatory responses in vitro. In Aim 3 we will define the effect of the role of Dectin-1 and NFAT signaling in innate and adaptive immune responses in vivo.