Adenosine Shapes Neonatal Toll-like Receptor Function

描述（由申请人提供）：新生儿感染风险增加，但其易感性的机制尚未完全确定。toll样受体（TLRs）在识别微生物成分中起着至关重要的作用，包括细菌脂肽（BLPs），由多种细菌表达，通过TLR1/2（三酰基化BLPs）或TLR2/6（二酰基化BLPs）的异源二聚体激活单核细胞。初步研究表明，尽管TLRs和相关信号成分的表达正常，但新生儿单核细胞在blp诱导的促炎和th1极化细胞因子肿瘤坏死因子- α (tnf - α)的合成中表现出2至3 log的损伤，而blp诱导的IL-6（一种具有抗炎和th2极化活性的细胞因子）的生成则保持不变。大肠杆菌K1/r（一种表达blp的致病菌）对新生儿tnf - α产生的类似损害也很明显。我们发现BLP和大肠杆菌诱导的新生儿血液单核细胞tnf - α生成受损可归因于血浆腺苷的作用，腺苷是一种内源性嘌呤代谢物，具有免疫调节特性，在应激或缺氧条件下从细胞中释放出来。新生儿单核细胞对腺苷诱导的tnf - α产生的抑制和腺苷诱导的环AMP的产生特别敏感，环AMP是一种细胞内代谢物，可抑制tnf - α合成，同时保留IL-6的产生。该项目的总体目标是表征新生儿腺苷系统在调节新生儿血液单核细胞中tlr介导的先天免疫反应中的作用。这一目标将通过三个具体目标来实现：(1)确定新生儿单核细胞更大的腺苷敏感性的机制，(2)确定介导抑制BLP和大肠杆菌诱导的新生儿血液单核细胞产生tnf - α的腺苷受体亚型；(3)表征腺苷受体参与导致BLP和大肠杆菌诱导的单核细胞tnf - α产生减少同时保持IL-6产生的机制。机制分析将确定腺苷如何改变新生儿tlr介导的免疫反应。总的来说，这些研究将加深我们对人类新生儿的独特生理如何从根本上改变出生时的先天免疫的理解。

DESCRIPTION (provided by applicant): Newborns are at increased risk of infection yet the mechanisms underlying their susceptibility are incompletely defined. Toll-like receptors (TLRs) play crucial roles in the recognition of microbial components including bacterial lipopeptides (BLPs), expressed by a wide-range of bacteria, that activate monocytes via a heterodimer of TLR1/2 (triacylated BLPs) or TLR2/6 (diacylated BLPs). Preliminary studies indicate that despite normal expression of TLRs and associated signaling components, human newborn blood monocytes demonstrate a 2- to 3-log impairment in BLP-induced synthesis of pro-inflammatory and Th1-polarizing cytokine tumor necrosis factor-alpha (TNF-alpha) with preservation of BLP-induced production of IL-6, a cytokine with anti-inflammatory and Th2-polarizing activities. Similar impairment in neonatal TNF-alpha production is evident in response to E. coli K1/r, a pathogenic bacterium that expresses BLPs. We have discovered that impaired BLP- and E. col1- induced TNF-alpha production from neonatal blood monocytes is attributable to the action of plasma adenosine, an endogenous purine metabolite with immunomodulatory properties that is released from cells under conditions of stress or hypoxia. Neonatal mononuclear cells are especially sensitive to adenosine-induced inhibition of TNF-alpha production and to adenosine-induced production of cyclic AMP, an intracellular metabolite that inhibits TNF-alpha synthesis while preserving IL-6 production. The overall goal of this project is to characterize the role of the neonatal adenosine system in modulating TLR-mediated innate immune responses in neonatal blood monocytes. This goal will be accomplished through three specific aims: (1) to determine the mechanism for the greater adenosine sensitivity of neonatal mononuclear cells, (2) to define the adenosine receptor sub-type(s) that mediate inhibition of BLP- and E. coli-induced TNF-alpha production from neonatal blood monocytes; and (3) to characterize the mechanism by which engagement of adenosine receptors results in diminished BLP- and E. coli-induced monocyte TNF-alpha production while preserving IL-6 production. Mechanistic analysis will define how adenosine alters neonatal TLR-mediated immune responses. As a whole, these studies will deepen our understanding of how the unique physiology of the human newborn fundamentally alters innate immunity at birth.