Role of extracellular microRNA-146a-5p in host innate immunity and bacterial sepsis
Sheng Wang,
Yang Yang,
Andrew Suen,
Jing Zhu,
Brittney Williams,
Jiang Hu,
Fengqian Chen,
Rosemary Kozar,
Shiqian Shen,
Ziyi Li,
Anjana Jeyaram,
Steven M. Jay,
Lin Zou,
Wei Chao
Affiliations
Sheng Wang
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Yang Yang
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Diagnostic Ultrasound, The Second Xiangya Hospital, Central South University, Changsha, China
Andrew Suen
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Anesthesia, Pain Management & Perioperative Medicine, Dalhousie University, Halifax, NS, Canada
Jing Zhu
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Brittney Williams
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Jiang Hu
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Fengqian Chen
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Rosemary Kozar
Program in Trauma & Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Shiqian Shen
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Ziyi Li
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Anjana Jeyaram
Fischell Department of Bioengineering, A James Clark School of Engineering, University of Maryland, College Park, MD 20742, USA
Steven M. Jay
Fischell Department of Bioengineering, A James Clark School of Engineering, University of Maryland, College Park, MD 20742, USA
Lin Zou
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Corresponding author
Wei Chao
Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Corresponding author
Summary: Extracellular miRNAs (ex-miRNAs) mediate intercellular communication and play a role in diverse physiological and pathological processes. Using small RNA sequencing, we identify that miRNAs are the most abundant RNA species in the plasma and differentially expressed in murine and human sepsis, such as miR-146a-5p. Exogenous miR-146a-5p, but not its duplex precursor, induces a strong immunostimulatory response through a newly identified UU-containing motif and TLR7 activation, and an immunotolerance by rapid IRAK-1 protein degradation via TLR7→MyD88 signaling and proteasome activation, whereas its duplex precursor acts by targeting 3′ UTR of Irak-1 gene via Ago2 binding. miR-146a knockout in mice offers protection against sepsis with attenuated interleukin-6 (IL-6) storm and organ injury, improved cardiac function, and better survival. In septic patients, the plasma miR-146a-5p concentrations are closely associated with the two sepsis outcome predictors, blood lactate and coagulopathy. These data demonstrate the importance of extracellular miR-146a-5p in innate immune regulation and sepsis pathogenesis.
