Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma

Authors

Andrew O Suen
Fengqian Chen
Sheng Wang
Ziyi Li
Jing Zhu
Yang Yang
Olivia Conn
Kerri Lopez
Ping Cui
Laurence Wechsler
Alan Cross
Gary Fiskum
Rosemary Kozar
Peter Hu
Catriona Miller
Lin Zou
Brittney Williams
Wei Chao

Publication Date

6-15-2023

Journal

The Journal of Immunology

Abstract

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma—bone fracture, muscle crush injury, and bowel ischemia—induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs (i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p) abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatic analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement production. Finally, compared with the wild-type, TLR7-knockout mice had attenuated plasma cytokine storm and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.

Keywords

Humans, Mice, Animals, Toll-Like Receptor 7, Disease Models, Animal, MicroRNAs, Inflammation, Cytokines, Multiple Trauma

DOI

10.4049/jimmunol.2300103

PMID

37133342

PMCID

PMC10235856

PubMedCentral® Posted Date

5-3-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes