{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:34:17Z","timestamp":1788834857001,"version":"build-2803163510"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Inflammatory bowel disease (IBD), characterized by chronic intestinal inflammation and epithelial barrier dysfunction, remains a therapeutic challenge due to the limitations of current treatments, including drug resistance and invasive surgical risks. Emerging evidence implicates intestinal epithelial cells (IECs) pyroptosis as a key contributor to IBD progression. Bone marrow mesenchymal stem cell exosomes (BMSCs-Exo) exhibit anti-inflammatory and tissue-reparative potential, yet the role of tumor necrosis factor-stimulated gene 6 (TSG-6), a critical anti-inflammatory mediator in BMSCs-Exo, in modulating pyroptosis and intestinal barrier integrity remains unexplored. This study investigates the role of TSG-6 contained in mesenchymal stem cell-derived exosomes (MSCs-Exo) in alleviating IBD by modulating the pyroptosis signaling pathway in IECs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, TSG-6-enriched BMSCs-Exo significantly alleviated intestinal inflammation and pyroptosis in murine IBD models. BMSCs-Exo administration reduced NLRP3 inflammasome activation, suppressed Caspase-1-mediated Gasdermin D (GSDMD) cleavage, and decreased pro-inflammatory cytokine release (IL-1\u03b2, IL-18). Notably, TSG-6 knockdown in BMSCs-Exo abolished these protective effects, confirming its essential role in blocking the NLRP3\/Caspase-1\/GSDMD axis. Furthermore, BMSCs-Exo restored intestinal barrier integrity by upregulating tight junction proteins (e.g., ZO-1, occludin) and reducing epithelial permeability. <jats:italic>In vitro<\/jats:italic> experiments revealed that BMSCs-Exo directly inhibited pyroptosis in IECs, attenuating cell membrane rupture and inflammatory cascade amplification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study identifies TSG-6 as a pivotal mediator in BMSCs-Exo that disrupts pyroptosis-driven IBD pathogenesis by targeting NLRP3 inflammasome activation. The findings highlight BMSCs-Exo as a cell-free therapeutic strategy to mitigate intestinal inflammation and barrier damage, offering advantages over traditional MSCs-based therapies in safety and specificity. By elucidating the TSG-6\/NLRP3 regulatory axis, this work provides a novel framework for developing exosome-engineered treatments for IBD and other pyroptosis-related inflammatory disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1601591","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T04:10:44Z","timestamp":1751256644000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6"],"prefix":"10.3389","volume":"16","author":[{"given":"Bihua","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyan","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghao","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenglin","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2015.1982","article-title":"Inflammatory bowel disease in children and adolescents","volume":"169","author":"Rosen","year":"2015","journal-title":"JAMA Pediatr"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.1103713","article-title":"The epidemiology of inflammatory bowel disease: clues to pathogenesis","volume":"10","author":"Borowitz","year":"2022","journal-title":"Front Pediatr"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(17)32448-0","article-title":"Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies","volume":"390","author":"Ng","year":"2017","journal-title":"Lancet (London England)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ueg2.12634","article-title":"Natural course of ulcerative colitis in China: differences from the west","volume":"12","author":"Wan","year":"2024","journal-title":"United Eur Gastroenterol J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00276","article-title":"Nlrp3 inflammasome and inflammatory bowel disease","volume":"10","author":"Zhen","year":"2019","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1038\/s41419-019-2157-1","article-title":"Nek7 interacts with nlrp3 to modulate the pyroptosis in inflammatory bowel disease via nf-\u03bab signaling","volume":"10","author":"Chen","year":"2019","journal-title":"Cell Death Dis"},{"key":"B7","article-title":"Cell death of intestinal epithelial cells in intestinal diseases","volume":"72","author":"Subramanian","year":"2020","journal-title":"Sheng li xue bao: [Acta physiologica Sinica]"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2013.158","article-title":"Immunobiology of mesenchymal stem cells","volume":"21","author":"Ma","year":"2014","journal-title":"Cell Death differentiation"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.108698","article-title":"Immunotherapy of inflammatory bowel disease (Ibd) through mesenchymal stem cells","volume":"107","author":"Huldani","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"784","DOI":"10.3390\/cells8080784","article-title":"Mesenchymal stem cell migration and tissue repair","volume":"8","author":"Fu","year":"2019","journal-title":"Cells"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2021.0094","article-title":"Mesenchymal stem cells: potential therapeutic prospect of paracrine pathways in neonatal infection","volume":"41","author":"Miao","year":"2021","journal-title":"J Interferon Cytokine research: Off J Int Soc Interferon Cytokine Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.117296","article-title":"Exosome-based nanoparticles and cancer immunotherapy","volume":"179","author":"Ye","year":"2024","journal-title":"Biomedicine pharmacotherapy = Biomedecine pharmacotherapie"},{"key":"B13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s13287-023-03345-0","article-title":"Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing","volume":"14","author":"Zhou","year":"2023","journal-title":"Stem Cell Res Ther"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1154217","article-title":"Exosome and virus infection","volume":"14","author":"Peng","year":"2023","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajps.2022.100772","article-title":"Therapeutic potential of exosome-based personalized delivery platform in chronic inflammatory diseases","volume":"18","author":"Wang","year":"2023","journal-title":"Asian J Pharm Sci"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.749192","article-title":"Effects of mesenchymal stem cell-derived exosomes on autoimmune diseases","volume":"12","author":"Shen","year":"2021","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"10434","DOI":"10.3390\/ijms241310434","article-title":"Adipose tissue-derived mesenchymal stem cell-derived exosomes promote wound healing and tissue regeneration","volume":"24","author":"Lee","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1186\/s13287-021-02492-6","article-title":"Hucmsc-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the mir-378a-5p\/nlrp3 axis","volume":"12","author":"Cai","year":"2021","journal-title":"Stem Cell Res Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-022-01577-z","article-title":"Bone marrow mesenchymal stem cells-derived exosomes containing mir-539-5p inhibit pyroptosis through nlrp3\/caspase-1 signalling to alleviate inflammatory bowel disease","volume":"71","author":"Wang","year":"2022","journal-title":"Inflammation research: Off J Eur Histamine Res Soc [et al]"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30275","article-title":"Adipose-derived mesenchymal stem cell-secreted exosome alleviates dextran sulfate sodium-induced acute colitis by treg cell induction and inflammatory cytokine reduction","volume":"236","author":"Heidari","year":"2021","journal-title":"J Cell Physiol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e131273","DOI":"10.1172\/jci.insight.131273","article-title":"Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism","volume":"4","author":"Liu","year":"2019","journal-title":"JCI Insight"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.14336\/ad.2021.0601","article-title":"Human adipose mesenchymal stem cell-derived exosomes protect mice from dss-induced inflammatory bowel disease by promoting intestinal-stem-cell and epithelial regeneration","volume":"12","author":"Yu","year":"2021","journal-title":"Aging Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.matbio.2018.01.011","article-title":"Tsg-6: A multifunctional protein with anti-inflammatory and tissue-protective properties","author":"Day","year":"2019","journal-title":"Matrix biology: J Int Soc Matrix Biol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s12974-020-1731-x","article-title":"Anti-inflammatory protein tsg-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the tlr2\/myd88\/nf-\u03bab signaling pathway in spinal microglia","volume":"17","author":"Yang","year":"2020","journal-title":"J Neuroinflamm"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2023.148466","article-title":"Tsg-6 alleviates cerebral ischemia\/reperfusion injury and blood-brain barrier disruption by suppressing er stress-mediated inflammation","volume":"1817","author":"Cui","year":"2023","journal-title":"Brain Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-021-03375-1","article-title":"Tumor necrosis factor-stimulated gene-6 (Tsg-6) secreted by bmscs regulates activated astrocytes by inhibiting nf-\u03bab signaling pathway to ameliorate blood brain barrier damage after intracerebral hemorrhage","volume":"46","author":"Tang","year":"2021","journal-title":"Neurochemical Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2023.126651","article-title":"Anti-inflammatory protein tsg-6 secreted by bmscs attenuates silica-induced acute pulmonary inflammation by inhibiting nlrp3 inflammasome signaling in macrophages","volume":"253","author":"Su","year":"2023","journal-title":"Int J Biol macromolecules"},{"key":"B28","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1186\/s13287-021-02404-8","article-title":"A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via tsg-6","volume":"12","author":"Yang","year":"2021","journal-title":"Stem Cell Res Ther"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.221","article-title":"A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow","volume":"4","author":"Soleimani","year":"2009","journal-title":"Nat Protoc"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1193","article-title":"Ncbi geo: archive for functional genomics data sets\u2013update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1092","article-title":"Kegg: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics: J Integr Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9133-4_19","article-title":"Exosomes from cell culture-conditioned medium: isolation by ultracentrifugation and characterization","volume":"1952","author":"Purushothaman","year":"2019","journal-title":"Methods Mol Biol (Clifton NJ)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.03.042","article-title":"Network pharmacology-based identification of the protective mechanisms of taraxasterol in experimental colitis","volume":"71","author":"Chen","year":"2019","journal-title":"Int Immunopharmacol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1039\/d2bm00559j","article-title":"Mesenchymal stem cell-derived exosome mitigates colitis via the modulation of the gut metagenomics-metabolomics-farnesoid X receptor axis","volume":"10","author":"Ocansey","year":"2022","journal-title":"Biomaterials Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.27222","article-title":"Irinotecan disrupts tight junction proteins within the gut: implications for chemotherapy-induced gut toxicity","volume":"15","author":"Wardill","year":"2014","journal-title":"Cancer Biol Ther"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1998.00728.x","article-title":"Chronic experimental colitis induced by dextran sulphate sodium (Dss) is characterized by th1 and th2 cytokines","volume":"114","author":"Dieleman","year":"1998","journal-title":"Clin Exp Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s43588-023-00464-9","article-title":"Single-cell meta-analysis of inflammatory bowel disease with scibd","volume":"3","author":"Nie","year":"2023","journal-title":"Nat Comput Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2022.113247","article-title":"Exosome-mediated mir-4655-3p contributes to uv radiation-induced bystander effects","volume":"418","author":"Wang","year":"2022","journal-title":"Exp Cell Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1039\/d3mh01030a","article-title":"Plant exosome nanovesicles (Pens): green delivery platforms","volume":"10","author":"Cao","year":"2023","journal-title":"Materials horizons"},{"key":"B41","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1186\/s13287-022-03174-7","article-title":"Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of il-17(+) regulatory T cell","volume":"13","author":"Zhang","year":"2022","journal-title":"Stem Cell Res Ther"},{"key":"B42","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1038\/s41419-022-05305-7","article-title":"Bone marrow mesenchymal stem cell-derived exosomal mir-21a-5p alleviates renal fibrosis by attenuating glycolysis by targeting pfkm","volume":"13","author":"Xu","year":"2022","journal-title":"Cell Death Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115488","article-title":"Bone marrow mesenchymal stem cell exosome-derived lncrna tuc339 influences the progression of osteoarthritis by regulating synovial macrophage polarization and chondrocyte apoptosis","volume":"167","author":"Shen","year":"2023","journal-title":"Biomedicine pharmacotherapy = Biomedecine pharmacotherapie"},{"key":"B44","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1186\/s13287-019-1436-1","article-title":"Tsg-6 in Conditioned Media from Adipose Mesenchymal Stem Cells Protects against Visual Deficits in Mild Traumatic Brain Injury Model through Neurovascular Modulation","volume":"10","author":"Jha","year":"2019","journal-title":"Stem Cell Res Ther"},{"key":"B45","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/s41419-022-05445-w","article-title":"Mesenchymal stem\/stromal cells primed by inflammatory cytokines alleviate psoriasis-like inflammation via the tsg-6-neutrophil axis","volume":"13","author":"Ding","year":"2022","journal-title":"Cell Death Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2024.103717","article-title":"Intestinal mucus barrier: A potential therapeutic target for ibd","volume":"24","author":"Qiao","year":"2025","journal-title":"Autoimmun Rev"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ai.2014.11.003","article-title":"Epithelial cell contributions to intestinal immunity","volume":"126","author":"Hooper","year":"2015","journal-title":"Adv Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1178662","article-title":"Gasdermin D-mediated pyroptosis: mechanisms, diseases, and inhibitors","volume":"14","author":"Dai","year":"2023","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2023.116846","article-title":"Tou nong powder obstructs ulcerative colitis through the regulation of nf-\u03bab\/nlrp3\/caspase-1\/gsdmd inflammasome pyroptotic pathway","volume":"317","author":"Ye","year":"2023","journal-title":"J ethnopharmacology"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.18449","article-title":"Malat1 promotes colonic epithelial cell apoptosis and pyroptosis by sponging mir-22-3p to enhance nlrp3 expression","volume":"12","author":"Yan","year":"2024","journal-title":"PeerJ"},{"key":"B51","doi-asserted-by":"publisher","first-page":"619","DOI":"10.3390\/v16040619","article-title":"Mesenchymal stem cell-derived exosomes attenuate murine cytomegalovirus-infected pneumonia via nf-\u03bab\/nlrp3 signaling pathway","volume":"16","author":"Chen","year":"2024","journal-title":"Viruses"},{"key":"B52","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s13287-018-0841-1","article-title":"Tsg-6 released from intraperitoneally injected canine adipose tissue-derived mesenchymal stem cells ameliorate inflammatory bowel disease by inducing M2 macrophage switch in mice","volume":"9","author":"Song","year":"2018","journal-title":"Stem Cell Res Ther"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izz192","article-title":"Effectiveness and safety of the sequential use of a second and third anti-tnf agent in patients with inflammatory bowel disease: results from the eneida registry","volume":"26","author":"Casanova","year":"2020","journal-title":"Inflammatory bowel Dis"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.3390\/cells8121605","article-title":"Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases","volume":"8","author":"Harrell","year":"2019","journal-title":"Cells"},{"key":"B55","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/s41392-022-01263-w","article-title":"Mir146a-loaded engineered exosomes released from silk fibroin patch promote diabetic wound healing by targeting irak1","volume":"8","author":"Li","year":"2023","journal-title":"Signal transduction targeted Ther"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202201105","article-title":"Mesenchymal stem cell exosomes encapsulated oral microcapsules for acute colitis treatment","volume":"11","author":"Gan","year":"2022","journal-title":"Advanced healthcare materials"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-019-0563-2","article-title":"Engineered exosomes for targeted co-delivery of mir-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer","volume":"18","author":"Liang","year":"2020","journal-title":"J nanobiotechnology"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1601591\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T04:10:45Z","timestamp":1751256645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1601591\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,30]]},"references-count":57,"alternative-id":["10.3389\/fimmu.2025.1601591"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1601591","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,30]]},"article-number":"1601591"}}