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Neutrophils can release NETs spontaneously; however, the mechanisms underlying spontaneous NETosis remain unclear. Neutrophils isolated from healthy donors were tested for NET formation and autophagy at 1, 6, 12, and 24\u00a0h after incubation. Autophagy response was evaluated in response to various autophagy inducers and inhibitors. The relationship between autophagy and NETosis was detected in vivo using an ovalbumin-induced mouse model of asthma. We found that the increase in the proportion of spontaneous NETosis was time-dependent. The number of autophagy-positive cells also increased over time and LC3B protein played an integral role in NET formation. Trehalose (an inducer of mTOR-independent autophagy) treatment significantly increased NET formation, whereas rapamycin (an mTOR-dependent autophagy inducer) did not increase NET release by neutrophils. Compared with the control group, 3-methyladenine (an autophagy sequestration inhibitor) and hydroxychloroquine sulfate (autophagosome-lysosome fusion inhibitor) treatments significantly reduced the percentage of NET-positive cells. In vivo studies on ovalbumin-induced asthma lung sections revealed NETs and LC3B and citH3 proteins were found to co-localize with DNA. Our findings suggest that autophagy plays a crucial role in aging-related spontaneous NETosis.<\/jats:p>","DOI":"10.1038\/s41598-021-03520-4","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T06:03:55Z","timestamp":1639461835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Spontaneous formation of neutrophil extracellular traps is associated with autophagy"],"prefix":"10.1038","volume":"11","author":[{"given":"Yun","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"3520_CR1","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nri.2017.10","volume":"17","author":"O Soehnlein","year":"2017","unstructured":"Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagonists and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248\u2013261. https:\/\/doi.org\/10.1038\/nri.2017.10 (2017).","journal-title":"Nat. Rev. Immunol."},{"key":"3520_CR2","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1080\/17476348.2019.1654377","volume":"13","author":"MJ Hughes","year":"2019","unstructured":"Hughes, M. J., Sapey, E. & Stockley, R. Neutrophil phenotypes in chronic lung disease. Expert Rev. Respir. Med. 13, 951\u2013967. https:\/\/doi.org\/10.1080\/17476348.2019.1654377 (2019).","journal-title":"Expert Rev. Respir. Med."},{"key":"3520_CR3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a037028","author":"SS Burgener","year":"2019","unstructured":"Burgener, S. S. & Schroder, K. Neutrophil extracellular traps in host defense. Cold Spring Harb. Perspect. Biol. https:\/\/doi.org\/10.1101\/cshperspect.a037028 (2019).","journal-title":"Cold Spring Harb. Perspect. 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