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However, it remains unclear how CTB activates immune cells. We here evaluated whether or how CTB induces production of a pro-inflammatory cytokine, interleukin-1\u03b2 (IL-1\u03b2). CTB induced IL-1\u03b2 production not only from bone marrow-derived macrophages (BMMs) but also from resident peritoneal macrophages in synergy with O111:B4-derived lipopolysaccharide (LPS O111:B4) that can bind to CTB. Meanwhile, when prestimulated with O55:B5-derived LPS (LPS O55:B5) that fails to bind to CTB, resident peritoneal macrophages, but not BMMs, produced IL-1\u03b2 in response to CTB. The CTB-induced IL-1\u03b2 production in synergy with LPS in both peritoneal macrophages and BMMs was dependent on ganglioside GM1, which is required for internalization of CTB. Notably, not only the NLRP3 inflammasome but also the pyrin inflammasome were involved in CTB-induced IL-1\u03b2 production from resident peritoneal macrophages, while only the NLRP3 inflammasome was involved in that from BMMs. In response to CTB, a Rho family small GTPase, RhoA, which activates pyrin inflammasome upon various kinds of biochemical modification, increased its phosphorylation at serine-188 in a GM1-dependent manner. This phosphorylation as well as CTB-induced IL-1\u03b2 productions were dependent on protein kinase A (PKA), indicating critical involvement of PKA-dependent RhoA phosphorylation in CTB-induced IL-1\u03b2 production. Taken together, these results suggest that CTB, incorporated through GM1, can activate resident peritoneal macrophages to produce IL-1\u03b2 in synergy with LPS through novel mechanisms in which pyrin as well as NLRP3 inflammasomes are involved.<\/jats:p>","DOI":"10.1093\/intimm\/dxz004","type":"journal-article","created":{"date-parts":[[2019,1,23]],"date-time":"2019-01-23T10:22:57Z","timestamp":1548238977000},"page":"657-668","source":"Crossref","is-referenced-by-count":19,"title":["Cholera toxin B induces interleukin-1\u03b2 production from resident peritoneal macrophages through the pyrin inflammasome as well as the NLRP3 inflammasome"],"prefix":"10.1093","volume":"31","author":[{"given":"Takashi","family":"Orimo","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"},{"name":"Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University , Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5080-8356","authenticated-orcid":false,"given":"Izumi","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Hemmi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiya","family":"Ozasa","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Fukuda-Ohta","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomokazu","family":"Ohta","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mio","family":"Morinaka","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Kitauchi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Laboratory for Immune Regulation, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei-ichi","family":"Katayama","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University , Wakayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Keio University , Tsuruoka, Yamagata, Japan"},{"name":"Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology , Kawasaki, Kanagawa, Japan"},{"name":"Transborder Medical Research Center, University of Tsukuba , Tsukuba, Ibaraki, Japan"},{"name":"PRESTO, Japan Science and Technology Agency , Kawaguchi, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Miyake","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Immunoparasitology, Research Institute for Microbial Diseases, WPI Immunology Frontier Research Center, Osaka University , Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Host Defense, Research Institute for Microbial Diseases, Osaka University , Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Lifelong Sports and Health Sciences, Chubu University College of Life and Health Sciences , Kasugai, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsushi","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition , Ibaraki, Osaka, Japan"},{"name":"Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University , Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6728-3872","authenticated-orcid":false,"given":"Ken J","family":"Ishii","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition , Ibaraki, Osaka, Japan"},{"name":"Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University , Suita, Osaka, 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Immunol."},{"key":"2022071007561590000_CIT0005","doi-asserted-by":"crossref","first-page":"5982","DOI":"10.1016\/j.vaccine.2009.07.071","article-title":"Oral MucoRice expressing double-mutant cholera toxin A and B subunits induces toxin-specific neutralising immunity","volume":"27","author":"Yuki","year":"2009","journal-title":"Vaccine"},{"key":"2022071007561590000_CIT0006","doi-asserted-by":"crossref","first-page":"10638","DOI":"10.1073\/pnas.1002348107","article-title":"Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax","volume":"107","author":"Datta","year":"2010","journal-title":"Proc. Natl Acad. Sci. 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Int."},{"key":"2022071007561590000_CIT0009","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature10558","article-title":"Non-canonical inflammasome activation targets caspase-11","volume":"479","author":"Kayagaki","year":"2011","journal-title":"Nature"},{"key":"2022071007561590000_CIT0010","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1126\/science.1240248","article-title":"Noncanonical inflammasome activation by intracellular LPS independent of TLR4","volume":"341","author":"Kayagaki","year":"2013","journal-title":"Science"},{"key":"2022071007561590000_CIT0011","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1126\/science.1240988","article-title":"Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock","volume":"341","author":"Hagar","year":"2013","journal-title":"Science"},{"key":"2022071007561590000_CIT0012","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nature13683","article-title":"Inflammatory caspases are innate immune receptors for intracellular LPS","volume":"514","author":"Shi","year":"2014","journal-title":"Nature"},{"key":"2022071007561590000_CIT0013","doi-asserted-by":"crossref","first-page":"10662","DOI":"10.1073\/pnas.93.20.10662","article-title":"Mice with disrupted GM2\/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system","volume":"93","author":"Takamiya","year":"1996","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022071007561590000_CIT0014","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1002\/eji.200324135","article-title":"Cholera toxin activates dendritic cells through dependence on GM1-ganglioside which is mediated by NF-kappaB translocation","volume":"33","author":"Kawamura","year":"2003","journal-title":"Eur. J. 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J. Immunol"}],"container-title":["International Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/31\/10\/657\/44792527\/dxz004.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/31\/10\/657\/44792527\/dxz004.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T23:30:02Z","timestamp":1694561402000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/intimm\/article\/31\/10\/657\/5301773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,25]]},"references-count":30,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,1,25]]},"published-print":{"date-parts":[[2019,9,18]]}},"URL":"https:\/\/doi.org\/10.1093\/intimm\/dxz004","relation":{},"ISSN":["1460-2377"],"issn-type":[{"value":"1460-2377","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,10]]},"published":{"date-parts":[[2019,1,25]]}}}