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The diffusible signal factor (DSF) family represents a type of quorum-sensing signals found in diverse Gram-negative bacterial pathogens. Recent evidence shows that the DSF is involved in interkingdom communications between the bacterial pathogen and the host plant. In this study, we explored the anti-inflammatory effect of the DSF and its underlying molecular mechanism in a zebrafish model. We found that the DSF treatment exhibited a strong protective effect on the inflammatory response of zebrafish induced by lipopolysaccharide (LPS). In the LPS-induced inflammation zebrafish model, the DSF could significantly ameliorate the intestinal pathological injury, reduce abnormal migration and the aggregation of inflammatory cells, inhibit the excessive production of inflammatory mediator reactive oxygen species (ROS) content, and prevent apoptosis. Through an RNA-Seq analysis, a total of 938 differentially expressed genes (DEGs) was screened between LPS and LPS + DSF treatment zebrafish embryos. A further bioinformatics analysis and validation revealed that the DSF might inhibit the LPS-induced zebrafish inflammatory response by preventing the activation of signaling in the Toll-like receptor pathway, attenuating the expression of pro-inflammatory cytokines and chemokines, and regulating the activation of the caspase cascade through restoring the expression of lysosomal cathepsins and apoptosis signaling. This study, for the first time, demonstrates the anti-inflammatory role and a potential pharmaceutical application of the bacterial signal DSF. These findings also suggest that the interkingdom communication between DSF-producing bacteria and zebrafish might occur in nature.<\/jats:p>","DOI":"10.3390\/ijms23137110","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T09:00:13Z","timestamp":1656234013000},"page":"7110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Bacterial Quorum-Sensing Signal DSF Inhibits LPS-Induced Inflammations by Suppressing Toll-like Receptor Signaling and Preventing Lysosome-Mediated Apoptosis in Zebrafish"],"prefix":"10.3390","volume":"23","author":[{"given":"Hongjie","family":"Zhu","sequence":"first","affiliation":[{"name":"Zebrafish Model Research Center for Human Diseases and Drug Screening in Western China, School of Medicine, The College of Life Sciences, Northwest University, Xi\u2019an 710069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Wang","sequence":"additional","affiliation":[{"name":"Zebrafish Model Research Center for Human Diseases and Drug Screening in Western China, School of Medicine, The College of Life Sciences, Northwest University, Xi\u2019an 710069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Zebrafish Model Research Center for Human Diseases and Drug Screening in Western China, School of Medicine, The College of Life Sciences, Northwest University, Xi\u2019an 710069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbo","family":"Lu","sequence":"additional","affiliation":[{"name":"Zebrafish Model Research Center for Human Diseases and Drug Screening in Western China, School of Medicine, The College of Life Sciences, Northwest University, Xi\u2019an 710069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Wen","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Development Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6912-7673","authenticated-orcid":false,"given":"Jing","family":"Tian","sequence":"additional","affiliation":[{"name":"Zebrafish Model Research Center for Human Diseases and Drug Screening in Western China, School of Medicine, The College of Life Sciences, Northwest University, Xi\u2019an 710069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.cell.2010.03.006","article-title":"Inflammation 2010: New adventures of an old flame","volume":"140","author":"Medzhitov","year":"2010","journal-title":"Cell"},{"key":"ref_2","first-page":"74","article-title":"Identifying and defusing weapons of mass inflammation in carcinogenesis","volume":"1765","author":"Hofseth","year":"2006","journal-title":"Biochim. 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