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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A subclass of acylated anti-inflammatory mediators usurp Toll-like receptor 2 to inhibit neutrophil recruitment through peroxisome proliferator-activated receptor γ
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A subclass of acylated anti-inflammatory mediators usurp Toll-like receptor 2 to inhibit neutrophil recruitment through peroxisome proliferator-activated receptor γ

机译：酰化抗炎介质的一个子类篡夺Toll样受体2通过过氧化物酶体增殖物激活受体γ抑制嗜中性白细胞募集

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摘要

Toll-like receptors are host sentinel receptors that signal the presence of infectious nonself and initiate protective immunity. One of the primary immune defense mechanisms is the recruitment of neutrophils from the bloodstream into the infected tissue. Although neutrophils are important in host defense, they can also be responsible for damaging pathologies associated with excessive inflammation. Here, we report that the di-acylated TLR2 ligand lipoteichoic acid can directly inhibit neutrophil recruitment in vivo. This discovery allowed us to test the concept that conventional proinflammatory TLR2 ligands can be made to act as. inhibitors through specific structural modifications. Indeed, lipopeptide TLR2 ligands, when modified at their acyl chains to contain linoleate, lose their capacity to induce inflammation and yield ligands that can directly inhibit the in vivo neutrophil recruitment initiated by a wide range of proinflammatory stimuli. The inhibitory capacity of LTA and these modified ligands requires the expression of TLR2, but is independent of the TLR2 signaling adaptor, MyD88. Instead, this inhibitory effect requires functional activity of the fatty acid and nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ). Therefore, these data support a model in TLR2 biology where structural modifications of these ligands can profoundly influence host-microbial interactions. These inhibitory TLR2 ligands also have broader implications with respect to their potential use in various inflammatory disease settings.
机译：Toll样受体是宿主前哨受体，可发出感染性非自身信号并启动保护性免疫。主要的免疫防御机制之一是嗜中性粒细胞从血液中募集到感染的组织中。尽管中性粒细胞在宿主防御中很重要，但它们也可能导致与过度炎症相关的病理损害。在这里，我们报告说，双酰化TLR2配体脂蛋白酸可以直接抑制体内嗜中性粒细胞的募集。这一发现使我们能够测试可以使常规促炎性TLR2配体发挥作用的概念。抑制剂通过特定的结构修饰。实际上，脂肽TLR2配体在其酰基链上修饰为包含亚油酸酯时，会失去诱导炎症的能力，并产生可直接抑制由广泛的促炎性刺激引发的体内嗜中性白细胞募集的配体。 LTA和这些修饰的配体的抑制能力需要TLR2的表达，但独立于TLR2信号转导适配器MyD88。相反，这种抑制作用需要脂肪酸和核激素受体过氧化物酶体增殖物激活的受体γ（PPARγ）的功能活性。因此，这些数据支持了TLR2生物学中的模型，其中这些配体的结构修饰可深刻影响宿主-微生物相互作用。这些抑制性TLR2配体在各种炎症性疾病中的潜在用途方面也具有更广泛的意义。

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    Elizabeth M. Long; Alexander C. Klimowicz; Heitor A. Paula-Neto; Brandie Millen; Donna-Marie McCaffeity; Paul Kubes; Stephen M. Robbins;

  • 作者单位

    Southern Alberta Cancer Research Institute, Departments of Oncology and Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Southern Alberta Cancer Research Institute, Departments of Oncology and Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Calvin, Phoebe and Joan Snyder Institute of Inflammation, Infection and Immunity, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Calvin, Phoebe and Joan Snyder Institute of Inflammation, Infection and Immunity, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Calvin, Phoebe and Joan Snyder Institute of Inflammation, Infection and Immunity, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Calvin, Phoebe and Joan Snyder Institute of Inflammation, Infection and Immunity, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1;

    Southern Alberta Cancer Research Institute, Departments of Oncology and Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    inflammation; leukocyte recruitment; bacterial ligands; innate immunity;

    机译：炎;白细胞募集;细菌配体先天免疫;

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