{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T11:37:49Z","timestamp":1777721869477,"version":"3.51.4"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage <jats:italic>in vivo<\/jats:italic>. Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis.<\/jats:p><jats:p>Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.<\/jats:p>","DOI":"10.3389\/fimmu.2022.869207","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T06:00:20Z","timestamp":1657692020000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Acinar Cell-Derived Extracellular Vesicle MiRNA-183-5p Aggravates Acute Pancreatitis by Promoting M1 Macrophage Polarization Through Downregulation of FoxO1"],"prefix":"10.3389","volume":"13","author":[{"given":"De-sheng","family":"Tang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-sheng","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-tao","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-yu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Le","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-long","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-min","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nian-sheng","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.01.268","article-title":"Early Intra-Acinar Events in Pathogenesis of Pancreatitis","volume":"156","author":"Saluja","year":"2019","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2014.00117","article-title":"Cell Death and DAMPs in Acute Pancreatitis","volume":"20","author":"Kang","year":"2014","journal-title":"Mol Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.08.071","article-title":"Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis","volume":"153","author":"Gukovskaya","year":"2017","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2991","DOI":"10.1111\/bph.15026","article-title":"Myeloid-Specific Dopamine D2 Receptor Signalling Controls Inflammation in Acute Pancreatitis via Inhibiting M1 Macrophage","volume":"177","author":"Han","year":"2020","journal-title":"Br J Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.102920","article-title":"Macrophage Phenotypic Switch Orchestrates the Inflammation and Repair\/Regeneration Following Acute Pancreatitis Injury","volume":"58","author":"Wu","year":"2020","journal-title":"EBioMedicine"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6977","article-title":"The Biology, Function, and Biomedical Applications of Exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2019.10.049","article-title":"Exosomes From Mmu_Circ_0001359-Modified ADSCs Attenuate Airway Remodeling by Enhancing FoxO1 Signaling-Mediated M2-Like Macrophage Activation","volume":"19","author":"Shang","year":"2020","journal-title":"Mol Ther Nucleic Acids"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-019-0349-y","article-title":"Exosomal miRNA-19b-3p of Tubular Epithelial Cells Promotes M1 Macrophage Activation in Kidney Injury","volume":"27","author":"Lv","year":"2020","journal-title":"Cell Death Differ"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.08.164","article-title":"MiR-21-3p Aggravates Injury in Rats With Acute Hemorrhagic Necrotizing Pancreatitis by Activating TRP Signaling Pathway","volume":"107","author":"Wang","year":"2018","journal-title":"BioMed Pharmacother"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00686","article-title":"MiRNA-155 Regulates the Th17\/Treg Ratio by Targeting SOCS1 in Severe Acute Pancreatitis","volume":"9","author":"Wang","year":"2018","journal-title":"Front Physiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01488","article-title":"Emodin Alleviates Sodium Taurocholate-Induced Pancreatic Acinar Cell Injury via MicroRNA-30a-5p-Mediated Inhibition of High-Temperature Requirement A\/Transforming Growth Factor Beta 1 Inflammatory Signaling","volume":"8","author":"Xiang","year":"2017","journal-title":"Front Immunol"},{"key":"B12","article-title":"Secreted Klotho From Exosomes Alleviates Inflammation and Apoptosis in Acute Pancreatitis","volume":"11","author":"Wang","year":"2019","journal-title":"Am J Transl Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/s0039-6060(96)80299-6","article-title":"Interleukin-10 Prevents Death in Lethal Necrotizing Pancreatitis in Mice","volume":"120","author":"Kusske","year":"1996","journal-title":"Surgery"},{"key":"B14","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/s41419-019-1545-x","article-title":"Inhibition of miR-155 Reduces Impaired Autophagy and Improves Prognosis in an Experimental Pancreatitis Mouse Model","volume":"10","author":"Wan","year":"2019","journal-title":"Cell Death Dis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0278-3","article-title":"Inhibition of RIPK1-Dependent Regulated Acinar Cell Necrosis Provides Protection Against Acute Pancreatitis via the RIPK1\/NF-Kappab\/AQP8 Pathway","volume":"51","author":"Duan","year":"2019","journal-title":"Exp Mol Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12928","article-title":"Hydrogen Sulphide Exacerbates Acute Pancreatitis by Over-Activating Autophagy via AMPK\/mTOR Pathway","volume":"20","author":"Ji","year":"2016","journal-title":"J Cell Mol Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/4363672","article-title":"Hypoxia-Inducible Factor-1alpha Knockdown Plus Glutamine Supplementation Attenuates the Predominance of Necrosis Over Apoptosis by Relieving Cellular Energy Stress in Acute Pancreatitis","volume":"2019","author":"Ji","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"B18","doi-asserted-by":"publisher","first-page":"19887","DOI":"10.1038\/s41598-019-56220-5","article-title":"Acute Pancreatitis Promotes the Generation of Two Different Exosome Populations","volume":"9","author":"Jimenez-Alesanco","year":"2019","journal-title":"Sci Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165685","article-title":"Plasma-Derived Exosomes Contribute to Pancreatitis-Associated Lung Injury by Triggering NLRP3-Dependent Pyroptosis in Alveolar Macrophages","volume":"1866","author":"Wu","year":"2020","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-012718","article-title":"Diversity, Mechanisms, and Significance of Macrophage Plasticity","volume":"15","author":"Locati","year":"2020","journal-title":"Annu Rev Pathol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1053\/j.gastro.2019.09.040","article-title":"NLRP3 Inflammasome Regulates Development of Systemic Inflammatory Response and Compensatory Anti-Inflammatory Response Syndromes in Mice With Acute Pancreatitis","volume":"158","author":"Sendler","year":"2020","journal-title":"Gastroenterology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1714209","article-title":"Autophagy-Dependent Ferroptosis Drives Tumor-Associated Macrophage Polarization via Release and Uptake of Oncogenic KRAS Protein","volume":"16","author":"Dai","year":"2020","journal-title":"Autophagy"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00871","article-title":"Breast Cancer-Derived Exosomes Alter Macrophage Polarization via Gp130\/STAT3 Signaling","volume":"9","author":"Ham","year":"2018","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.02.038","article-title":"Controlled Diesel Exhaust and Allergen Coexposure Modulates microRNA and Gene Expression in Humans: Effects on Inflammatory Lung Markers","volume":"138","author":"Rider","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2018.6118","article-title":"Expression Profile of microRNAs Following Bone Marrow-Derived Mesenchymal Stem Cell Treatment in Lipopolysaccharide-Induced Acute Lung Injury","volume":"15","author":"Park","year":"2018","journal-title":"Exp Ther Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.13361","article-title":"Dysregulation of Genes and microRNAs in Localized Aggressive Periodontitis","volume":"47","author":"Goncalves Fernandes","year":"2020","journal-title":"J Clin Periodontol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02530","article-title":"Mucosal Immunity and the FOXO1 Transcription Factors","volume":"10","author":"Graves","year":"2019","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-00695-7","article-title":"Functional Crosstalk Between Myeloid Foxo1-Beta-Catenin Axis and Hedgehog\/Gli1 Signaling in Oxidative Stress Response","volume":"28","author":"Li","year":"2021","journal-title":"Cell Death Differ"},{"key":"B29","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s13287-020-01643-5","article-title":"High Cholesterol Induces Apoptosis and Autophagy Through the ROS-Activated AKT\/FOXO1 Pathway in Tendon-Derived Stem Cells","volume":"11","author":"Li","year":"2020","journal-title":"Stem Cell Res Ther"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2017.11.030","article-title":"The Regulation of FOXO1 and its Role in Disease Progression","volume":"193","author":"Xing","year":"2018","journal-title":"Life Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31050","article-title":"Lipotoxic Hepatocyte-Derived Exosomal MicroRNA 192-5p Activates Macrophages Through Rictor\/Akt\/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease","volume":"72","author":"Liu","year":"2020","journal-title":"Hepatology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13143","article-title":"Tissue-Resident Innate Immunity in the Lung","volume":"159","author":"Ardain","year":"2020","journal-title":"Immunology"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.869207\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T06:00:23Z","timestamp":1657692023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.869207\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,13]]},"references-count":32,"alternative-id":["10.3389\/fimmu.2022.869207"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.869207","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,13]]},"article-number":"869207"}}