Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
Nature. 2018 Jul;559(7712):114-119. doi: 10.1038/s41586-018-0253-5. Epub 2018 Jun 27.
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') characterized by reduced inflammatory cytokine output, increased secondary infection and an increased risk of organ failure and mortality. Lipopolysaccharide tolerance recapitulates several key features of sepsis-associated immunosuppression. Although various epigenetic changes have previously been observed in tolerized macrophages, 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.
长期暴露于微生物产物，如脂多糖，可诱导一种先天免疫记忆形式，使随后对无关病原体的反应减弱，这种现象被称为脂多糖耐受。败血症是一种失调的全身免疫反应，可导致传播性感染，其死亡率很高。在一些患者中，败血症会导致一段时间的免疫抑制（称为“免疫麻痹”），其特征是炎症细胞因子输出减少、二次感染增加以及器官衰竭和死亡率增加。脂多糖耐受可再现败血症相关免疫抑制的几个关键特征。尽管以前在耐受巨噬细胞中观察到了各种表观遗传变化，但耐受、免疫麻痹和其他形式的先天免疫记忆的分子基础仍不清楚。在这里，我们进行了耐受相关 microRNA 的筛选，并确定 miR-221 和 miR-222 是脂多糖耐受过程中巨噬细胞功能重编程的调节因子。在小鼠中，用脂多糖长时间刺激会导致 miR-221 和 mir-222 的表达增加，这两者都调节 brahma-related gene 1（也称为 Smarca4）。这种表达增加导致依赖于 SWI/SNF（转换/蔗糖非发酵）和 STAT（信号转导和转录激活因子）介导的染色质重塑的一组炎症基因的转录沉默，这反过来又促进了耐受。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相关。我们的研究结果表明，特定的 microRNAs 可以调节巨噬细胞耐受，并且可能作为败血症患者免疫麻痹和预后不良的生物标志物。
