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

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Amaral, Eduardo P. ^[1] ; Riteau, Nicolas ^[1] ; Moayeri, Mahtab ^[1] ; Maier, Nolan ^[1] ; Mayer-Barber, Katrin D. ^[2] ; Pereira, Rosana M. ^[3] ; Lage, Silvia L. ^[4] ; Kubler, Andre ^{[5, 6]} ; Bishai, William R. ^[6] ; D'Imperio-Lima, Maria R. ^[3] ; Sher, Alan ^[1] ; Andrade, Bruno B. ^{[7, 8, 1, 9, 10, 11, 12]}

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^[1] NIAID, Immunobiol Sect, Lab Parasit Dis Natl, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[2] NIAID, Inflammat & Innate Immun Unit, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Lab Immunol Infect Dis, Sao Paulo - Brazil

^[4] NIAID, Clin & Mol Retrovirol Sect, Lab Immunoregulat, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[5] Imperial Coll London, Dept Med, London - England

^[6] Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD - USA

^[7] Escola Bahiana Med & Saude Publ, Salvador, BA - Brazil

^[8] Fundacao Oswaldo Cruz, Inst Goncalo Moniz, Salvador, BA - Brazil

^[9] Jose Silveira Fdn, Multinatl Org Network Sponsoring Translat & Epide, Salvador, BA - Brazil

^[10] Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town - South Africa

^[11] Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, Nashville, TN 37212 - USA

^[12] Univ Salvador UNIFACS, Laureate Univ, Salvador, BA - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 9, JUN 21 2018.
• Citações Web of Science: 6

Resumo

Lysosomal 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-1 beta 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-1 beta. 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-1 beta 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-1 beta processing by regulating NLRP3-inflammasome assembly in the cytosol. (AU)

• Processo FAPESP: 13/07298-5 - Avaliação do envolvimento de catepsinas lisossomais na ativação do inflamassoma NLRP3 induzida por ESAT-6 recombinante de Mycobacterium tuberculosis
• Beneficiário: Eduardo Pinheiro Amaral
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado