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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\u2014bone fracture, muscle crush injury, and bowel ischemia\u2014induced 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 (&amp;gt;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.<\/jats:p>","DOI":"10.4049\/jimmunol.2300103","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T13:33:21Z","timestamp":1683120801000},"page":"1990-2000","source":"Crossref","is-referenced-by-count":11,"title":["Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma"],"prefix":"10.1093","volume":"210","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4354-6498","authenticated-orcid":false,"given":"Andrew O","family":"Suen","sequence":"first","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"},{"name":"Department of Anesthesia, Pain Management & Perioperative Medicine, Dalhousie University , Halifax, NS,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengqian","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-0533","authenticated-orcid":false,"given":"Ziyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center , Houston, TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Conn","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerri","family":"Lopez","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Cui","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence","family":"Wechsler","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4362-9936","authenticated-orcid":false,"given":"Alan","family":"Cross","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5909-0539","authenticated-orcid":false,"given":"Gary","family":"Fiskum","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9198-7351","authenticated-orcid":false,"given":"Rosemary","family":"Kozar","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Hu","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7243-8058","authenticated-orcid":false,"given":"Catriona","family":"Miller","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"},{"name":"Enroute Care Division, Department of Aeromedical Research, U.S. Air Force School of Aerospace Medicine, Wright Patterson Air Force Base , Dayton, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0820-4246","authenticated-orcid":false,"given":"Lin","family":"Zou","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brittney","family":"Williams","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2505-1360","authenticated-orcid":false,"given":"Wei","family":"Chao","sequence":"additional","affiliation":[{"name":"Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine , Baltimore, 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