Adenosine Shapes Neonatal Toll-like Receptor Function

腺苷塑造新生儿 Toll 样受体功能

• 批准号: 8108312
• 负责人: OFER LEVY
• 金额: $ 24.06万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108312
• 关键词: Adenosine; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Bacteria; Biological Preservation; Birth; Cell physiology; Cells; Complex; Cyclic AMP; Escherichia coli; Frequencies; Goals; Human; Hypoxia; Immune response; Immunologic Memory; Impairment; Infection; Inflammatory; Interleukin-6; Mediating; Modeling; Mononuclear; Natural Immunity; Nature; Neonatal; Newborn Infant; Physiology; Plasma; Play; Predisposition; Production; Property; Purine Nucleosides; Purinergic P1 Receptors; Purines; Risk; Role; Severities; Shapes; Signal Transduction; Signaling Molecule; Stimulus; Stress; System; TLR2 gene; TLR4 gene; Toll-Like Receptor 1; Toll-like receptors; Tumor Necrosis Factor-alpha; Umbilical Cord Blood; Vaccination; age group; cytokine; human TNF protein; insight; microbial; monocyte; novel strategies; pathogen; pathogenic bacteria; prevent; purine; receptor; receptor function; response

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.

描述（由申请人提供）：新生儿感染的风险增加，但其易感性的机制尚未完全确定。 Toll 样受体 (TLR) 在识别微生物成分中发挥着至关重要的作用，包括由多种细菌表达的细菌脂肽 (BLP)，通过 TLR1/2（三酰化 BLP）或 TLR2/6（二酰化 BLP）异二聚体激活单核细胞。初步研究表明，尽管 TLR 和相关信号成分表达正常，但人类新生儿血单核细胞在 BLP 诱导的促炎细胞因子和 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 个对数级的损伤，同时保留了 BLP 诱导的 IL-6（一种具有抗炎作用的细胞因子）的产生。 和 Th2 极化活动。大肠杆菌 K1/r（一种表达 BLP 的病原菌）对新生儿 TNF-α 产生的类似损害也很明显。我们发现，BLP ​​和 E. col1 诱导的新生儿血液单核细胞 TNF-α 产生受损可归因于血浆腺苷的作用，腺苷是一种具有免疫调节特性的内源性嘌呤代谢物，在应激或缺氧条件下从细胞中释放。新生儿单核细胞对腺苷诱导的 TNF-α 产生抑制和腺苷诱导的环 AMP 产生特别敏感，环 AMP 是一种抑制 TNF-α 合成同时保留 IL-6 产生的细胞内代谢物。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对腺苷敏感性更高的机制，（2）确定介导抑制新生儿血液单核细胞中 BLP 和大肠杆菌诱导的 TNF-α 产生的腺苷受体亚型； (3) 描述腺苷受体的参与导致 BLP 和大肠杆菌诱导的单核细胞 TNF-α 产生减少同时保留 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独特的生理机能如何从根本上改变出生时的先天免疫的理解。

项目成果

Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life.

• DOI: 10.1016/j.clim.2009.07.003
• 发表时间: 2009-11
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Belderbos ME;van Bleek GM;Levy O;Blanken MO;Houben ML;Schuijff L;Kimpen JL;Bont L
• 通讯作者: Bont L

Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors.

• DOI: 10.1371/journal.pone.0033419
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Belderbos ME;Levy O;Stalpers F;Kimpen JL;Meyaard L;Bont L
• 通讯作者: Bont L

Distinct TLR-mediated cytokine production and immunoglobulin secretion in human newborn naïve B cells.

• DOI: 10.1177/1753425916651985
• 发表时间: 2016-08
• 期刊: Innate immunity
• 影响因子: 3.2
• 作者: Pettengill MA;van Haren SD;Li N;Dowling DJ;Bergelson I;Jans J;Ferwerda G;Levy O
• 通讯作者: Levy O

Safety and efficacy of neonatal vaccination.

• DOI: 10.1002/eji.200838620
• 发表时间: 2009-01
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Demirjian, Alicia;Levy, Ofer
• 通讯作者: Levy, Ofer

Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.

• DOI: 10.1097/md.0b013e3181fd8ec3
• 发表时间: 2010-11
• 期刊: Medicine
• 影响因子: 1.6
• 作者: Picard C;von Bernuth H;Ghandil P;Chrabieh M;Levy O;Arkwright PD;McDonald D;Geha RS;Takada H;Krause JC;Creech CB;Ku CL;Ehl S;Maródi L;Al-Muhsen S;Al-Hajjar S;Al-Ghonaium A;Day-Good NK;Holland SM;Gallin JI;Chapel H;Speert DP;Rodriguez-Gallego C;Colino E;Garty BZ;Roifman C;Hara T;Yoshikawa H;Nonoyama S;Domachowske J;Issekutz AC;Tang M;Smart J;Zitnik SE;Hoarau C;Kumararatne DS;Thrasher AJ;Davies EG;Bethune C;Sirvent N;de Ricaud D;Camcioglu Y;Vasconcelos J;Guedes M;Vitor AB;Rodrigo C;Almazán F;Méndez M;Aróstegui JI;Alsina L;Fortuny C;Reichenbach J;Verbsky JW;Bossuyt X;Doffinger R;Abel L;Puel A;Casanova JL
• 通讯作者: Casanova JL