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.

Grant Number: 5R35GM140822-05
NIH Institute/Center: NIH
Principal Investigator: WEI CHAO