Ly6G+ neutrophil-derived miR-223 inhibits the NLRP3 inflammasome in mitochondrial DAMP-induced acute lung injury

• Published in: Cell death & disease Vol. 8; no. 11; p. e3170
• Main Authors: Feng, Zunyong, Qi, Shimei, Zhang, Yue, Qi, Zhilin, Yan, Liang, Zhou, Jing, He, Fang, Li, Qianqian, Yang, Yanyan, Chen, Qun, Xiao, Shi, Li, Qiang, Chen, Yang, Zhang, Yao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/21; 13/31; 14/105; 38/109; 38/90; 631/250/256/2177; 631/337/384/331; 631/80/86; 64/60; 692/699/1785; 82/29; 82/80; Acute Lung Injury - genetics; Acute Lung Injury - immunology; Acute Lung Injury - pathology; Adult; Animals; Antibodies; Antigens, Ly - genetics; Antigens, Ly - immunology; Biochemistry; Biomedical and Life Sciences; Bone marrow; Case-Control Studies; Cell activation; Cell Biology; Cell Culture; Cytokines; Female; Humans; IL-1β; Immunology; Inflammasomes; Inflammasomes - immunology; Inflammation; Interleukin-1beta - immunology; Leukocytes (neutrophilic); Life Sciences; Male; Mice; Mice, Inbred C57BL; MicroRNAs - immunology; Middle Aged; miRNA; Mitochondria; Mitochondria, Muscle - genetics; Mitochondria, Muscle - immunology; Neutrophils; Neutrophils - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; Original; original-article; Remission; Respiratory distress syndrome; Respiratory therapy; RNA-mediated interference; Signal transduction; Transfection; Trauma
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.549

MicroRNA (miRNA) mediates RNA interference to regulate a variety of innate immune processes, but how miRNAs coordinate the mechanisms underlying acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with pulmonary inflammatory injury is still unknown. In this study, we demonstrated that miR-223 limits the number of Ly6G+ neutrophils and inhibits the activity of the NLRP3 inflammasome to alleviate ALI induced by mitochondrial damage-associated molecular patterns (DAMPs) (MTDs). miR-223 expression is increased in the lungs of MTD-induced mice or ARDS patients following trauma/transfusion or following the physiological remission of ALI/ARDS. miR-223−/+ mice exhibited more severe ALI and cytokine dysregulation. Other studies have shown that MTD-induced increases in miR-223 expression are mainly contributed by Ly6G+ neutrophils from the haematopoietic system. miR-223 blocks bone marrow-derived Ly6G+ neutrophil differentiation and inhibits peripheral cytokine release. In addition, MTD-induced miR-223 expression activates a negative feedback pathway that targets the inhibition of NLRP3 expression and IL-1 β release; therefore, miR-223 deficiency can lead to the sustained activation of NLRP3-IL-1 β . Finally, elimination of peripheral Ly6G+ neutrophils and pharmacological blockade of the miR-223–NLRP3–IL-1 β signalling axis could alleviate MTD-induced ALI. In summary, miR-223 is essential for regulating the pathogenesis of DAMP-induced ALI.