Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages

dc.creatorAmaral, Eduardo Pinheiro
dc.creatorRiteau, Nicolas
dc.creatorMoayeri, Mahtab
dc.creatorMaier, Nolan
dc.creatorBarber, Katrin D. Mayer
dc.creatorPereira, Rosana M
dc.creatorLage, Silvia L
dc.creatorKubler, Andre
dc.creatorBishai, William R
dc.creatorLima, Maria R. D’Império
dc.creatorSher, Alan
dc.creatorAndrade, Bruno de Bezerril
dc.date2018-07-04T17:38:33Z
dc.date2018-07-04T17:38:33Z
dc.date2018
dc.date.accessioned2023-09-26T20:38:16Z
dc.date.available2023-09-26T20:38:16Z
dc.identifierAMARAL, E. P. et al. Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages. Frontiers in Immunology, v. 9, p. 1427, 2018.
dc.identifier1664-3224
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/27287
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8861078
dc.descriptionIntramural Research Program of the NIAID and by a grant from the National Institutes of Health (NIH) U01AI115940. EA received fellowship from São Paulo Research Foundation (2013/07298-5). The rabbit study was supported by the Howard Hughes Medical Institute (to WB) and the NIH (R01 AI 079590, R01 AI037856, and R01 AI036973 to WB).
dc.descriptionLysosomal cathepsin B (CTSB) has been proposed to play a role in the induction of acute inflammation. We hypothesised that the presence of active CTSB in the cytosol is crucial for NLRP3-inflammasome assembly and, consequently, for mature IL-1β generation after mycobacterial infection in vitro. Elevated levels of CTSB was observed in the lungs of mice and rabbits following infection with Mycobacterium tuberculosis (Mtb) H37Rv as well as in plasma from acute tuberculosis patients. H37Rv-infected murine bone marrow-derived macrophages (BMDMs) displayed both lysosomal leakage, with release of CTSB into the cytosol, as well as increased levels of mature IL-1β. These responses were diminished in BMDM infected with a mutant H37Rv deficient in ESAT-6 expression. Pharmacological inhibition of cathepsin activity with CA074-Me resulted in a substantial reduction of both mature IL-1β production and caspase-1 activation in infected macrophages. Moreover, cathepsin inhibition abolished the interaction between NLRP3 and ASC, measured by immunofluorescence imaging in H37Rv-infected macrophages, demonstrating a critical role of the enzyme in NLRP3-inflammasome activation. These observations suggest that during Mtb infection, lysosomal release of activated CTSB and possibly other cathepsins inhibitable by CA07-Me is critical for the induction of inflammasome-mediated IL-1β processing by regulating NLRP3-inflammasome assembly in the cytosol.
dc.formatapplication/pdf
dc.languageeng
dc.publisherFrontiers Media
dc.rightsopen access
dc.subjectCatepsina B
dc.subjectTuberculose
dc.subjectIL-1β
dc.subjectInflamassoma
dc.subjectSistema de secreção ESAT-6
dc.subjectCathepsin B
dc.subjectTuberculosis
dc.subjectIL-1β
dc.subjectInflammasome
dc.subjectESAT-6 secretion system
dc.titleLysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages
dc.typeArticle


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