{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:27:40Z","timestamp":1790144860015,"version":"4.0.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014857","name":"National Natural Science Foundation of China-Guangdong Joint Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014857","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To explore the role of the Nlrp3 inflammasome activation in the development of hemolytic uremic syndrome (HUS) induced by Stx2 and evaluate the efficacy of small molecule Nlrp3 inhibitors in preventing the HUS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peritoneal macrophages (PMs) isolated from wild-type (WT) C57BL\/6J mice and gene knockout mice (<jats:italic>Nlrc4<\/jats:italic><jats:sup>-\/-<\/jats:sup>,<jats:italic>Aim2<\/jats:italic><jats:sup>-\/-<\/jats:sup>, and<jats:italic>Nlrp3<\/jats:italic><jats:sup>-\/-<\/jats:sup>) were treated with Stx2<jats:italic>in vitro<\/jats:italic>and their IL-1\u03b2 releases were measured. WT mice and<jats:italic>Nlrp3<\/jats:italic><jats:sup>-\/-<\/jats:sup>mice were also treated with Stx2<jats:italic>in vivo<\/jats:italic>by injection, and the biochemical indices (serum IL-1\u03b2, creatinine [CRE] and blood urea nitrogen [BUN]), renal injury, and animal survival were compared. To evaluate the effect of the Nlrp3 inhibitors in preventing HUS, WT mice were pretreated with different Nlrp3 inhibitors (MCC950, CY-09, Oridonin) before Stx2 treatment, and their biochemical indices and survival were compared with the WT mice without inhibitor pretreatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>When PMs were stimulated by Stx2<jats:italic>in vitro<\/jats:italic>, IL-1\u03b2 release in<jats:italic>Nlrp3<\/jats:italic><jats:sup>-\/-<\/jats:sup>PMs was significantly lower compared to the other PMs. The<jats:italic>Nlrp3<\/jats:italic><jats:sup>-\/-<\/jats:sup>mice treated by Stx2<jats:italic>in vivo<\/jats:italic>, showed lower levels of the biochemical indices, alleviated renal injuries, and increased survival rate. When the WT mice were pretreated with the Nlrp3 inhibitors, both the biochemical indices and survival were significantly improved compared to those without inhibitor pretreatment, with Oridonin being most potent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Nlrp3 inflammasome activation plays a vital role in the HUS development when mice are challenged by Stx2, and Oridonin is effective in preventing HUS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2020.619096","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T06:47:48Z","timestamp":1611211668000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Activation of the Nlrp3 Inflammasome Contributes to Shiga Toxin-Induced Hemolytic Uremic Syndrome in a Mouse Model"],"prefix":"10.3389","volume":"11","author":[{"given":"Liqiong","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchun","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxun","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.59.11.4173-4179.1991","article-title":"Shiga toxin-associated hemolytic-uremic syndrome: combined cytotoxic effects of Shiga toxin, interleukin-1 beta, and tumor necrosis factor alpha on human vascular endothelial cells in vitro","volume":"59","author":"Louise","year":"1991","journal-title":"Infect Immun"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)74232-X","article-title":"Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome","volume":"365","author":"Tarr","year":"2005","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.272.17.1349","article-title":"A multistate outbreak of Escherichia coli O157:H7-associated bloody diarrhea and hemolytic uremic syndrome from hamburgers. The Washington experience","volume":"272","author":"Bell","year":"1994","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1097\/00063110-199709000-00009","article-title":"Escherichia coli O157 infection disaster in Japan, 1996","volume":"4","author":"Yukioka","year":"1997","journal-title":"Eur J Emerg Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3321\/j.issn:0254-6450.2008.01.014","article-title":"[Molecular epidemiology of enterohaemorrhagic Esacherichia coli O157 in some areas in China]","volume":"29","author":"Wang","year":"2008","journal-title":"Zhonghua Liu Xing Bing Xue Za Zhi"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1106483","article-title":"Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany","volume":"365","author":"Frank","year":"2011","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.290.10.1360","article-title":"Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression","volume":"290","author":"Garg","year":"2003","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/175.3.611","article-title":"The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection","volume":"175","author":"Karpman","year":"1997","journal-title":"J Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/978-3-642-77238-2_4","article-title":"Shiga toxin: biochemistry, genetics, mode of action, and role in pathogenesis","volume":"180","author":"O\u2019Brien","year":"1992","journal-title":"Curr Top Microbiol Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/microbiolspec.EHEC-0011-2013","article-title":"Shiga Toxin (Verotoxin)-Producing Escherichia coli in Japan","volume":"5","author":"Terajima","year":"2014","journal-title":"Microbiol Spectr"},{"key":"B11","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/j.1432-1033.1988.tb13756.x","article-title":"Site of action of a Vero toxin (VT2) from Escherichia coli O157:H7 and of Shiga toxin on eukaryotic ribosomes. RNA N-glycosidase activity of the toxins","volume":"171","author":"Endo","year":"1988","journal-title":"Eur J Biochem"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/BF00857676","article-title":"Recent advances in understanding the pathogenesis of the hemolytic uremic syndromes","volume":"4","author":"Kaplan","year":"1990","journal-title":"Pediatr Nephrol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01182-10","article-title":"Shiga toxin subtypes display dramatic differences in potency","volume":"79","author":"Fuller","year":"2011","journal-title":"Infect Immun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/172.5.1397","article-title":"Specific interaction of Escherichia coli O157:H7-derived Shiga-like toxin II with human renal endothelial cells","volume":"172","author":"Louise","year":"1995","journal-title":"J Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1542\/pir.29-10-335","article-title":"Chronic kidney disease in children","volume":"29","author":"Whyte","year":"2008","journal-title":"Pediatr Rev"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2002.00502.x","article-title":"Differential tissue targeting and pathogenesis of verotoxins 1 and 2 in the mouse animal model","volume":"62","author":"Rutjes","year":"2002","journal-title":"Kidney Int"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-003-1395-7","article-title":"Hemolytic uremic syndrome induced by lipopolysaccharide and Shiga-like toxin","volume":"19","author":"Ikeda","year":"2004","journal-title":"Pediatr Nephrol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s004670050712","article-title":"Circulating inflammatory cytokine levels in hemolytic uremic syndrome","volume":"13","author":"Litalien","year":"1999","journal-title":"Pediatr Nephrol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01095-15","article-title":"Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1\u03b2 and Apoptotic Cell Death","volume":"84","author":"Lee","year":"2016","journal-title":"Infect Immun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2016.10.004","article-title":"Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death","volume":"42","author":"Shi","year":"2017","journal-title":"Trends Biochem Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400075111","article-title":"Bacterial RNA:DNA hybrids are activators of the NLRP3 inflammasome","volume":"111","author":"Kailasan Vanaja","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.071","article-title":"Shiga Toxin\/Lipopolysaccharide Activates Caspase-4 and Gasdermin D to Trigger Mitochondrial Reactive Oxygen Species Upstream of the NLRP3 Inflammasome","volume":"25","author":"Platnich","year":"2018","journal-title":"Cell Rep"},{"key":"B23","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41419-019-1413-8","article-title":"Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors","volume":"10","author":"Yang","year":"2019","journal-title":"Cell Death Dis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2013.00009","article-title":"Characterization of Shiga toxin-producing Escherichia coli O130:H11 and O178:H19 isolated from dairy cows","volume":"3","author":"Fern\u00e1ndez","year":"2013","journal-title":"Front Cell Infect Microbiol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00510","article-title":"A critical role for hemolysin in Vibrio fluvialis-induced IL-1\u03b2 secretion mediated by the NLRP3 inflammasome in macrophages","volume":"6","author":"Song","year":"2015","journal-title":"Front Microbiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V80.11.2755.bloodjournal80112755","article-title":"Tumor necrosis factor and interleukin-1 induce expression of the verocytotoxin receptor globotriaosylceramide on human endothelial cells: implications for the pathogenesis of the hemolytic uremic syndrome","volume":"80","author":"van de Kar","year":"1992","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.03071-14","article-title":"The Type VI Secretion System Modulates Flagellar Gene Expression and Secretion in Citrobacter freundii and Contributes to Adhesion and Cytotoxicity to Host Cells","volume":"83","author":"Liu","year":"2015","journal-title":"Infect Immun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nature02664","article-title":"Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf","volume":"430","author":"Mariathasan","year":"2004","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nature07725","article-title":"AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC","volume":"458","author":"Hornung","year":"2009","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.04.012","article-title":"A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses","volume":"30","author":"Meng","year":"2009","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2013.6","article-title":"Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock","volume":"23","author":"Mao","year":"2013","journal-title":"Cell Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1159\/000431333","article-title":"A pathological scoring system to predict renal outcome in diabetic nephropathy","volume":"41","author":"Hoshino","year":"2015","journal-title":"Am J Nephrol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1086\/318080","article-title":"Immunoprophylactic potential of cloned Shiga toxin 2 B subunit","volume":"183","author":"Marcato","year":"2001","journal-title":"J Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00918-15","article-title":"AB5 Preassembly Is Not Required for Shiga Toxin Activity","volume":"198","author":"Pellino","year":"2016","journal-title":"J Bacteriol"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.1681\/ASN.V94614","article-title":"Role of IL-1 in renal ischemic reperfusion injury","volume":"9","author":"Haq","year":"1998","journal-title":"J Am Soc Nephrol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000115704.86897.F4","article-title":"Contributions of IL-1beta and IL-1alpha to crescentic glomerulonephritis in mice","volume":"15","author":"Timoshanko","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.4","article-title":"IL-1 pathways in inflammation and human diseases","volume":"6","author":"Gabay","year":"2010","journal-title":"Nat Rev Rheumatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1997.170","article-title":"Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells","volume":"51","author":"van Setten","year":"1997","journal-title":"Kidney Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3806","article-title":"A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases","volume":"21","author":"Coll","year":"2015","journal-title":"Nat Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171419","article-title":"Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders","volume":"214","author":"Jiang","year":"2017","journal-title":"J Exp Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1038\/s41467-018-04947-6","article-title":"Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity","volume":"9","author":"He","year":"2018","journal-title":"Nat Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.619096\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T13:18:35Z","timestamp":1670851115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.619096\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,21]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2020.619096"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.619096","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,21]]},"article-number":"619096"}}