Extracellular miRNAs, innate immunity, and critical illness

项目摘要 脓毒症和缺血性心肌梗死(MI)是两种病死率很高的危重疾病。而他们的 病因明显不同，它们有相似的先天免疫激活特征，明显的组织 炎症和急性心功能不全。组织炎症，主要是由先天免疫激活驱动的， 是脓毒症和心肌缺血再灌注(I/R)时心脏损伤的主要决定因素。我们发现， 宿主细胞RNA和各种miRNAs在小鼠/人脓毒症和心肌梗死期间释放到血液中 循环宿主RNA与脓毒症的严重程度密切相关，并参与了心肌I/R损伤 动物。RNAseq显示，miRNAs是健康人和健康人血浆RNAs的主要生物型(70%) 败血症小鼠和人类。此外，我们已经报道了这些细胞外(EX)-RNA和某些富含尿苷的 Ex-miRNAs发挥损伤相关分子模式(DAMP)的作用，并驱动先天免疫反应 通过依赖TLR7的途径。利用计算机算法，我们已经鉴定了两个miRNA序列 已被证明是miRNA诱导的天然免疫激活所必需的基序。最后，TLR7基因缺失 减轻细胞因子风暴/凝血障碍，提高脓毒症动物的存活率。这项研究的目的是 该计划旨在阐明ex-miRNAs在天然免疫激活中的功能和机制 脓毒症与心肌I/R损伤的发病机制。具体来说，我们将解决以下3个关键问题：1) 前miRNAs在全身先天免疫激活和脓毒症心功能不全中的作用是什么？ 在I/R后的心肌炎症和梗死中？2)潜在的机制是什么 前-miRNA介导的脓毒症和心肌I/R时的心脏损伤和功能障碍？ 抗miRNA或抗TLR7策略可减轻脓毒症引起的心肌病并提高存活率，并 减少I/R后的心肌损伤？我们将使用脓毒症的小鼠模型和生物制品/临床数据 病人。这项拟议的工作代表了miRNA生物学的一种范式转变-它独特的功能是在 先天免疫和两种由先天免疫驱动的炎症主导的危重疾病。

Project Summary Sepsis and ischemic myocardial infarction (MI) are two critical illnesses with very high mortality. While their etiologies are distinctively different, they share similar features of innate immune activation, marked tissue inflammation, and acute cardiac dysfunction. Tissue inflammation, largely driven by innate immunity activation, is a major determinant of cardiac injury in sepsis and myocardial ischemia-reperfusion (I/R). We have found that host cellular RNA and various miRNAs are released into the blood during murine/human sepsis and myocardial I/R. Circulating host RNA is closely correlated with sepsis severity and contributes to myocardial I/R injury in animals. RNAseq reveals that miRNAs are the dominant biotype (70%) of plasma RNAs in both healthy and septic mice and human. Moreover, we have reported that these extracellular (ex)-RNAs and certain uridine-rich ex-miRNAs function as a damage-associated molecular pattern (DAMP) and drive innate immune response through a TLR7-dependent pathway. Using a computer algorithm, we have identified two miRNA sequence motifs proven to be essential for miRNA-induced innate immunity activation. Finally, genetic deletion of TLR7 attenuates cytokine storm/coagulopathy and improves survival in sepsis animals. The goal of this research program is to delineate the function and mechanism of ex-miRNAs in innate immunity activation and in the pathogenesis of sepsis and myocardial I/R injury. Specifically, we will address the following 3 key questions: 1) What are the roles of ex-miRNAs in systemic innate immunity activation and cardiac dysfunction in sepsis, and in myocardial inflammation and infarction following I/R? 2) What are the underlying mechanisms responsible for ex-miRNA-mediated cardiac injury and dysfunction during sepsis and myocardial I/R? 3) Can we develop an anti-miRNA or anti-TLR7 strategy to attenuate sepsis-induced cardiomyopathy and improve survival, and to reduce myocardial injury after I/R? We will use both mouse models and biospecimens/clinical data of septic patients. The proposed work represents a paradigm shift in miRNA biology – its unique function as a DAMP in innate immunity and in two critical illnesses that are dominated by innate immunity-driven inflammation.