{"doi":"10.4049/jimmunol.2300103","title":"Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma","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.","journal":"The Journal of Immunology","year":2023,"id":347747,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":438179,"name":"Fengqian Chen","orcid":"0000-0002-2330-6403","position":1,"is_corresponding":false},{"id":461367,"name":"Sheng Wang","orcid":"0000-0002-5625-403X","position":2,"is_corresponding":false},{"id":340429,"name":"Ziyi Li","orcid":"0000-0001-8359-0533","position":3,"is_corresponding":false},{"id":1089616,"name":"Jing Zhu","orcid":"0009-0008-7493-3555","position":4,"is_corresponding":false},{"id":461365,"name":"Yang Yang","orcid":"0000-0002-4178-1259","position":5,"is_corresponding":false},{"id":1090081,"name":"Olivia Conn","orcid":null,"position":6,"is_corresponding":false},{"id":766074,"name":"Kerri Lopez","orcid":null,"position":7,"is_corresponding":false},{"id":887955,"name":"Ping Cui","orcid":"0000-0002-1272-5661","position":8,"is_corresponding":false},{"id":1089617,"name":"Laurence Wechsler","orcid":"0000-0002-0975-463X","position":9,"is_corresponding":false},{"id":667496,"name":"Alan S. 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