PMID- 29977244 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1664-3224 (Print) IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 9 DP - 2018 TI - Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages. PG - 1427 LID - 10.3389/fimmu.2018.01427 [doi] LID - 1427 AB - 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-1beta 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-1beta. 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-1beta 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-1beta processing by regulating NLRP3-inflammasome assembly in the cytosol. FAU - Amaral, Eduardo P AU - Amaral EP AD - Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Riteau, Nicolas AU - Riteau N AD - Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Moayeri, Mahtab AU - Moayeri M AD - Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Maier, Nolan AU - Maier N AD - Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Mayer-Barber, Katrin D AU - Mayer-Barber KD AD - Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Pereira, Rosana M AU - Pereira RM AD - Laboratory of Immunology of Infectious Diseases, Department of Immunology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil. FAU - Lage, Silvia L AU - Lage SL AD - Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Kubler, Andre AU - Kubler A AD - Department of Medicine, Imperial College London, London, United Kingdom. AD - Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States. FAU - Bishai, William R AU - Bishai WR AD - Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States. FAU - D'Imperio-Lima, Maria R AU - D'Imperio-Lima MR AD - Laboratory of Immunology of Infectious Diseases, Department of Immunology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, Brazil. FAU - Sher, Alan AU - Sher A AD - Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. FAU - Andrade, Bruno B AU - Andrade BB AD - Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. AD - Instituto Goncalo Moniz, Fundacao Oswaldo Cruz, Salvador, Bahia, Brazil. AD - Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Jose Silveira Foundation, Salvador, Brazil. AD - Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. AD - Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States. AD - Universidade Salvador (UNIFACS), Laureate University, Salvador, Bahia, Brazil. AD - Escola Bahiana de Medicina e Saude Publica, Salvador, Bahia, Brazil. LA - eng GR - R01 AI036973/AI/NIAID NIH HHS/United States GR - R01 AI037856/AI/NIAID NIH HHS/United States GR - R01 AI079590/AI/NIAID NIH HHS/United States GR - U01 AI115940/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20180621 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 PMC - PMC6021483 OTO - NOTNLM OT - ESAT-6 secretion system OT - IL-1beta OT - cathepsin B OT - inflammasome OT - tuberculosis EDAT- 2018/07/07 06:00 MHDA- 2018/07/07 06:01 PMCR- 2018/01/01 CRDT- 2018/07/07 06:00 PHST- 2018/02/21 00:00 [received] PHST- 2018/06/08 00:00 [accepted] PHST- 2018/07/07 06:00 [entrez] PHST- 2018/07/07 06:00 [pubmed] PHST- 2018/07/07 06:01 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2018.01427 [doi] PST - epublish SO - Front Immunol. 2018 Jun 21;9:1427. doi: 10.3389/fimmu.2018.01427. eCollection 2018.