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However, the mechanism behind stress-induced gastrointestinal injury is not well understood. The objective of our study is to elucidate the putative mechanism of stress-induced gastrointestinal injury and develop an intervention strategy. To achieve this, we employed the restraint stress mouse model, a well-established method to study the pathophysiological changes associated with psychological stress in mice. By orally administering gut-nonabsorbable Evans blue dye and monitoring its plasma levels, we were able to track the progression of gastrointestinal injury in live mice. Additionally, flow cytometry was utilized to assess the viability, death, and inflammatory status of splenic leukocytes, providing insights into the stress-induced impact on the innate immune system associated with stress-induced gastrointestinal injury. Our findings reveal that neutrophils represent the primary innate immune leukocyte lineage responsible for stress-induced inflammation. Splenic neutrophils exhibited elevated expression levels of the pro-inflammatory cytokine IL-1, cellular reactive oxygen species, mitochondrial burden, and cell death following stress challenge compared to other innate immune cells such as macrophages, monocytes, and dendritic cells. Regulated cell death analysis indicated that NETosis is the predominant stress-induced cell death response among other analyzed regulated cell death pathways. NETosis culminates in the formation and release of neutrophil extracellular traps, which play a crucial role in modulating inflammation by binding to pathogens. Treatment with the NETosis inhibitor GSK484 rescued stress-induced neutrophil extracellular trap release and gastrointestinal injury, highlighting the involvement of neutrophil extracellular traps in stress-induced gastrointestinal inflammation. Our results suggest that neutrophil NETosis could serve as a promising drug target for managing psychological stress-induced gastrointestinal injuries.<\/jats:p>","DOI":"10.3390\/ijms25105261","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:03:08Z","timestamp":1715673788000},"page":"5261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Restraint Stress-Induced Neutrophil Inflammation Contributes to Concurrent Gastrointestinal Injury in Mice"],"prefix":"10.3390","volume":"25","author":[{"given":"Rina","family":"Munalisa","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Te-Sheng","family":"Lien","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Yeh","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1994-7355","authenticated-orcid":false,"given":"Der-Shan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0104-0146","authenticated-orcid":false,"given":"Ching-Feng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan"},{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8983-6458","authenticated-orcid":false,"given":"Wen-Sheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"},{"name":"Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Cheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddha Tzu Chi Medical Foundation, Hualien 970, Taiwan"},{"name":"Center of Stem Cell & Precision Medicine, Hualien Tzu Chi Hospital, Buddha Tzu Chi Medical Foundation, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6292-1521","authenticated-orcid":false,"given":"Chi-Tan","family":"Hu","sequence":"additional","affiliation":[{"name":"Research Center for Hepatology and Department of Gastroenterology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Wang","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yungling Leo","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan"},{"name":"College of Public Health, China Medical University, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chi","family":"Chou","sequence":"additional","affiliation":[{"name":"Biomedical Translation Research Center, Academia Sinica, Taipei 115, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8731-3485","authenticated-orcid":false,"given":"Hsin-Hou","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.4291\/wjgp.v4.i4.108","article-title":"Effects of occupational stress on the gastrointestinal tract","volume":"4","author":"Tienda","year":"2013","journal-title":"World J. 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