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ANR-10-IAHU-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["grant no. ANR-10-IAHU-01"],"award-info":[{"award-number":["grant no. ANR-10-IAHU-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013414","name":"Conseil R\u00e9gional des Pays de la Loire","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013414","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondation Raoul Follereau France"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Mycolactone, a lipid-like toxin, is the major virulence factor of <jats:italic>Mycobacterium ulcerans<\/jats:italic>, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by <jats:italic>M<\/jats:italic>. <jats:italic>ulcerans<\/jats:italic> induced the production of IL-1\u03b2, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3\/1 inflammasomes. We show our data to be relevant in a physiological context. The <jats:italic>in vivo<\/jats:italic> injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1\u03b2, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009107","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T18:29:45Z","timestamp":1608316185000},"page":"e1009107","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":47,"title":["Mycolactone toxin induces an inflammatory response by targeting the IL-1\u03b2 pathway: Mechanistic insight into Buruli ulcer pathophysiology"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6988-1112","authenticated-orcid":true,"given":"M.","family":"Foulon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7358-8173","authenticated-orcid":true,"given":"M.","family":"Robbe-Saule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5998-2051","authenticated-orcid":true,"given":"J.","family":"Manry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9467-5217","authenticated-orcid":true,"given":"L.","family":"Esnault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Boucaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1012-2226","authenticated-orcid":true,"given":"A.","family":"Alca\u00efs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9858-8716","authenticated-orcid":true,"given":"M.","family":"Malloci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1587-5147","authenticated-orcid":true,"given":"M.","family":"Fanton d\u2019Andon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Beauvais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-6546","authenticated-orcid":true,"given":"N.","family":"Labarriere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Jeannin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Abel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-0235","authenticated-orcid":true,"given":"J. 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mycobacteria","volume":"8","author":"MT Ruf","year":"2017","journal-title":"Virulence"},{"issue":"5","key":"ppat.1009107.ref017","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1021\/acschembio.7b00053","article-title":"The Macrolide Toxin Mycolactone Promotes Bim-Dependent Apoptosis in Buruli Ulcer through Inhibition of mTOR","volume":"12","author":"R Bieri","year":"2017","journal-title":"ACS chemical biology"},{"issue":"3","key":"ppat.1009107.ref018","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1365-2249.2006.03020.x","article-title":"The local immune response in ulcerative lesions of Buruli disease","volume":"143","author":"AE Kiszewski","year":"2006","journal-title":"Clin Exp Immunol"},{"issue":"10","key":"ppat.1009107.ref019","doi-asserted-by":"crossref","first-page":"6299","DOI":"10.1128\/IAI.73.10.6299-6310.2005","article-title":"Infection with Mycobacterium ulcerans induces persistent inflammatory responses in mice","volume":"73","author":"MS 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Producer","volume":"196","author":"E Marion","year":"2016","journal-title":"J Immunol"},{"issue":"8","key":"ppat.1009107.ref023","first-page":"S115","article-title":"Overview of atopic dermatitis","volume":"23","author":"C. Avena-Woods","year":"2017","journal-title":"The American journal of managed care"},{"issue":"1","key":"ppat.1009107.ref024","doi-asserted-by":"crossref","DOI":"10.1128\/CMR.00069-18","article-title":"Cutaneous Mycobacterial Infections","volume":"32","author":"C Franco-Paredes","year":"2018","journal-title":"Clin Microbiol Rev"},{"issue":"1","key":"ppat.1009107.ref025","doi-asserted-by":"crossref","first-page":"e44","DOI":"10.1016\/j.mycmed.2014.11.002","article-title":"Dermatomycoses and inflammation: The adaptive balance between growth, damage, and survival","volume":"25","author":"B Hube","year":"2015","journal-title":"Journal de mycologie medicale"},{"issue":"8","key":"ppat.1009107.ref026","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1128\/IAI.00290-07","article-title":"Mycolactone-mediated inhibition of tumor necrosis factor production by macrophages infected with Mycobacterium ulcerans has implications for the control of infection","volume":"75","author":"E Torrado","year":"2007","journal-title":"Infect Immun"},{"issue":"4","key":"ppat.1009107.ref027","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.4049\/jimmunol.0802294","article-title":"Mycolactone inhibits monocyte cytokine production by a posttranscriptional mechanism","volume":"182","author":"RE Simmonds","year":"2009","journal-title":"J Immunol"},{"issue":"7081","key":"ppat.1009107.ref028","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature04516","article-title":"Gout-associated uric acid crystals activate the NALP3 inflammasome","volume":"440","author":"F Martinon","year":"2006","journal-title":"Nature"},{"issue":"4","key":"ppat.1009107.ref029","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.cytogfr.2011.10.001","article-title":"Understanding the mechanism of IL-1beta secretion","volume":"22","author":"G Lopez-Castejon","year":"2011","journal-title":"Cytokine & growth factor 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