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Induction of innate immune memory via microRNA targeting of chromatin remodelling factors

机译：通过靶向染色质重塑因子的microRNA诱导先天免疫记忆

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摘要

Prolonged exposure to microbial products such as lipopolysaccharide can induce a form of innate immune memory that blunts subsequent responses to unrelated pathogens, known as lipopolysaccharide tolerance. Sepsis is a dysregulated systemic immune response to disseminated infection that has a high mortality rate. In some patients, sepsis results in a period of immunosuppression (known as 'immunoparalysis')(1) characterized by reduced inflammatory cytokine output(2), increased secondary infection(3) and an increased risk of organ failure and mortality(4). Lipopolysaccharide tolerance recapitulates several key features of sepsis-associated immunosuppression(5). Although various epigenetic changes have previously been observed in tolerized macrophages(6-8), the molecular basis of tolerance, immunoparalysis and other forms of innate immune memory has remained unclear. Here we perform a screen for tolerance-associated microRNAs and identify miR-221 and miR-222 as regulators of the functional reprogramming of macrophages during lipopolysaccharide tolerization. Prolonged stimulation with lipopolysaccharide in mice leads to increased expression of miR-221 and mir-222, both of which regulate brahma-related gene 1 (Brg1, also known as Smarca4). This increased expression causes the transcriptional silencing of a subset of inflammatory genes that depend on chromatin remodelling mediated by SWI/SNF (switch/sucrose non-fermentable) and STAT (signal transducer and activator of transcription), which in turn promotes tolerance. In patients with sepsis, increased expression of miR-221 and miR-222 correlates with immunoparalysis and increased organ damage. Our results show that specific microRNAs can regulate macrophage tolerization and may serve as biomarkers of immunoparalysis and poor prognosis in patients with sepsis.
机译：长时间暴露于微生物产品（如脂多糖）会诱导先天免疫记忆的形式，从而削弱对无关病原体的后续反应，即脂多糖耐受性。败血症是对弥散性感染的全身免疫反应失调，具有很高的死亡率。在某些患者中，败血症导致免疫抑制期（称为“免疫麻痹”）（1），其特征在于炎症性细胞因子输出减少（2），继发感染增加（3）以及器官衰竭和死亡的风险增加（4）。脂多糖耐受性概括了败血症相关免疫抑制的几个关键特征（5）。尽管以前已经在耐受的巨噬细胞中观察到各种表观遗传学变化（6-8），但尚不清楚耐受性，免疫麻痹和其他形式的先天免疫记忆的分子基础。在这里，我们进行了与耐受性相关的microRNA的筛选，并确定了miR-221和miR-222作为脂多糖耐受期间巨噬细胞功能性重编程的调节剂。小鼠中脂多糖的长期刺激导致miR-221和mir-222的表达增加，它们都调节婆罗门相关基因1（Brg1，也称为Smarca4）。这种增加的表达引起依赖于SWI / SNF（开关/不可发酵的蔗糖）和STAT（信号转导和转录激活因子）介导的染色质重塑的炎症基因子集的转录沉默。在败血症患者中，miR-221和miR-222的表达增加与免疫麻痹和器官损伤增加有关。我们的结果表明，特定的microRNA可以调节巨噬细胞的耐受性，并且可以作为脓毒症患者免疫麻痹和不良预后的生物标志物。

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  • 来源
    《Nature》 |2018年第7712期|114-119|共6页
  • 作者

    Seeley John J.; Baker Rebecca G.; Mohamed Ghait; Bruns Tony; Hayden Matthew S.; Deshmukh Sachin D.; Freedberg Daniel E.; Ghosh Sankar;

  • 作者单位

    Columbia Univ, Dept Microbiol & Immunol, New York, NY 10027 USA;

    Columbia Univ, Dept Microbiol & Immunol, New York, NY 10027 USA;

    Jena Univ Hosp, Integrated Res & Treatment Ctr Sepsis Control & C, Jena, Germany;

    Jena Univ Hosp, Integrated Res & Treatment Ctr Sepsis Control & C, Jena, Germany;

    Columbia Univ, Dept Microbiol & Immunol, New York, NY 10027 USA;

    Jena Univ Hosp, Integrated Res & Treatment Ctr Sepsis Control & C, Jena, Germany;

    Columbia Univ, Coll Phys & Surg, Dept Med, Div Digest & Liver Dis, New York, NY USA;

    Columbia Univ, Dept Microbiol & Immunol, New York, NY 10027 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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