ExRNA Takes a Toll in Sepsis-associated Lung Injury

Abstract

Following cell stress, injury, or infections, potentially injurious host-derived damageassociated molecular patterns (DAMPs) trigger the innate immune response. Among these DAMPs, the importance of extracellular nucleic acids, such as mitochondrial DNA and vesicleassociated non-coding RNA, in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), is increasingly recognized. Extracellular RNA is primarily composed of microRNA (miRNA) and ribosomal (rRNA) and can be vesicle-associated, protein-bound, or free form. These different forms of exRNA play roles in endothelial permeability and inflammation via recognition by receptors such as vascular endothelial growth factor receptor 2 (VEGFR-2) (1), receptor for advanced glycation end products (RAGE) (2), and toll-like receptors (TLRs). Plasma and alveolar extracellular RNA (exRNA) profiles are altered during lung injury and sepsis (3), and plasma microRNA-146-5p (miR146-5p) is elevated during sepsis (4). Given the diverse sequences and forms of exRNA and increasing interest in RNA-based therapeutics, understanding how some of these exRNAs contribute to lung injury or other diseases will advance our technology in applying RNA biology to mitigate inflammatory diseases and clinical syndromes including sepsis and acute lung injury.Here, Huang and colleagues report that extracellular miR146a-5p activates TLR7 in macrophages and induces vascular permeability via TNFα (5). miR146a-5p is a miRNA that negatively regulates TLR signaling intracellularly by silencing IRAK1/TRAF6 expression (6).However, the extracellular form of miR146a-5p is vesicle-associated and is proinflammatory in macrophages (7). Thus miR146a-5p fulfills the definition of a DAMP. In a cecal ligation and puncture-induced model of sepsis, miR146a-5p is elevated in both plasma and bronchoalveolar lavage. Intra-tracheal administration of miR146a-5p induced TLR7-dependent proinflammatory cytokine expression, endothelial disruption, and neutrophil recruitment. In vitro, conditioned