MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission
Abstract Modulation of miRNAs and neutrophil extracellular traps (NETs) formation are both implicated in inflammatory disorders. Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease with neutrophilic leukocytosis and unknown etiology. Although the NETs formation is elevated in A...
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Nature Portfolio
2021-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-95028-0 |
| _version_ | 1819126495611715584 |
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| author | Tsai-Ling Liao Yi-Ming Chen Kuo-Tung Tang Po-Ku Chen Hung-Jen Liu Der-Yuan Chen |
| author_facet | Tsai-Ling Liao Yi-Ming Chen Kuo-Tung Tang Po-Ku Chen Hung-Jen Liu Der-Yuan Chen |
| author_sort | Tsai-Ling Liao |
| collection | DOAJ |
| description | Abstract Modulation of miRNAs and neutrophil extracellular traps (NETs) formation are both implicated in inflammatory disorders. Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease with neutrophilic leukocytosis and unknown etiology. Although the NETs formation is elevated in AOSD patients, the regulatory roles of miRNAs in NETs formation in AOSD remains unclear. We revealed that the circulating levels of IL-18, NETs, and miR-223 were significantly higher in active AOSD patients, compared with inactive AOSD patients or healthy controls (P < 0.005). Moreover, IL-18 increased calcium influx into neutrophils, which led to mitochondrial ROS (mROS) production and NETs formation. Elevated levels of NETs-DNA could induce miR-223 expression in neutrophils through activating Toll-like receptor 9. The upregulated miR-223 expression in neutrophils suppressed mROS production by blocking calcium influx, and subsequently inhibited IL-18-mediated NETs formation. Besides, the increased neutrophil-derived exosomal miR-223 levels were observed in active AOSD patients compared with healthy controls (P < 0.005). Our in vitro assays demonstrated that the neutrophil-derived small extracellular vesicles carried miR-223, which could repress IL-18 production in macrophages. Together, these results suggest a fine-tuned mechanism between inflammatory (IL-18 induced NETs) and anti-inflammatory (miR-223) factors in AOSD. MiR-223, mROS inhibitors, and calcium channel blockers are the potential therapeutics for autoinflammatory diseases such as AOSD. |
| first_indexed | 2024-12-22T07:56:57Z |
| format | Article |
| id | doaj.art-a0f2a73a1f5b4c26b72c48c36aa6cdd4 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-22T07:56:57Z |
| publishDate | 2021-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a0f2a73a1f5b4c26b72c48c36aa6cdd42022-12-21T18:33:20ZengNature PortfolioScientific Reports2045-23222021-08-0111111710.1038/s41598-021-95028-0MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmissionTsai-Ling Liao0Yi-Ming Chen1Kuo-Tung Tang2Po-Ku Chen3Hung-Jen Liu4Der-Yuan Chen5Department of Medical Research, Taichung Veterans General HospitalDepartment of Medical Research, Taichung Veterans General HospitalDivision of Allergy, Immunology and Rheumatology, Taichung Veterans General HospitalRheumatology and Immunology Center, Department of Medicine, China Medical University HospitalRong Hsing Research Center for Translational Medicine, National Chung Hsing UniversityRheumatology and Immunology Center, Department of Medicine, China Medical University HospitalAbstract Modulation of miRNAs and neutrophil extracellular traps (NETs) formation are both implicated in inflammatory disorders. Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease with neutrophilic leukocytosis and unknown etiology. Although the NETs formation is elevated in AOSD patients, the regulatory roles of miRNAs in NETs formation in AOSD remains unclear. We revealed that the circulating levels of IL-18, NETs, and miR-223 were significantly higher in active AOSD patients, compared with inactive AOSD patients or healthy controls (P < 0.005). Moreover, IL-18 increased calcium influx into neutrophils, which led to mitochondrial ROS (mROS) production and NETs formation. Elevated levels of NETs-DNA could induce miR-223 expression in neutrophils through activating Toll-like receptor 9. The upregulated miR-223 expression in neutrophils suppressed mROS production by blocking calcium influx, and subsequently inhibited IL-18-mediated NETs formation. Besides, the increased neutrophil-derived exosomal miR-223 levels were observed in active AOSD patients compared with healthy controls (P < 0.005). Our in vitro assays demonstrated that the neutrophil-derived small extracellular vesicles carried miR-223, which could repress IL-18 production in macrophages. Together, these results suggest a fine-tuned mechanism between inflammatory (IL-18 induced NETs) and anti-inflammatory (miR-223) factors in AOSD. MiR-223, mROS inhibitors, and calcium channel blockers are the potential therapeutics for autoinflammatory diseases such as AOSD.https://doi.org/10.1038/s41598-021-95028-0 |
| spellingShingle | Tsai-Ling Liao Yi-Ming Chen Kuo-Tung Tang Po-Ku Chen Hung-Jen Liu Der-Yuan Chen MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission Scientific Reports |
| title | MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission |
| title_full | MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission |
| title_fullStr | MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission |
| title_full_unstemmed | MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission |
| title_short | MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission |
| title_sort | microrna 223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission |
| url | https://doi.org/10.1038/s41598-021-95028-0 |
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