Non-Toll-like receptor innate immune signaling

描述(申请人提供)：先天免疫受体触发炎症，激活微生物杀伤机制，并指导获得性免疫反应的发展。Toll样受体(Toll-like Receptor，TLR)家族是目前研究最完整的天然受体家族。这些受体在识别广泛的微生物产物、触发NF-B激活和产生大量细胞因子和趋化因子方面起着至关重要的作用，并已被证明是宿主有效防御许多病原体所必需的。然而，TLR并不能激活所有的天然宿主防御，额外的“非TLR”天然免疫受体触发吞噬作用，激活抗菌素杀伤机制，影响TLR信号转导的结果，对于有效的宿主防御可能同样重要。目前，对这些非TLR先天受体的研究很少。我们已经建立了β-葡聚糖受体Dectin-1作为一种基于非TLR的天然免疫识别模型。这种受体能激活含有葡聚糖的颗粒(如酵母)的吞噬作用，并激活抗菌活性氧种的产生。Dectin-1信号还与TLR信号一起协调细胞细胞因子和趋化因子的产生。虽然TLR信号与细胞因子受体信号有许多共同之处，但我们发现Dectin-1信号与抗原受体信号有许多共同之处。因此，通常与获得性免疫相关的信号通路，包括Src/Syk和NFAT(核因子激活的T细胞)通路，在暴露于酵母或酵母后在吞噬细胞中被激活。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的假设。 在目标1中，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的Src家族激酶和Syk的机制。在目标2中，我们将探讨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，我们将确定Dectin-1和NFAT信号在体内先天和获得性免疫反应中的作用。

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.