Extracellular miRNAs, innate immunity, and critical illness

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.