title: Pre-exposure of Mycobacterium tuberculosis-infected macrophages to crystalline silica impairs control of bacterial growth by deregulating the balance between apoptosis and necrosis.
abstract: Inhalation of crystalline silica (CS) particles increases the risk of pulmonary tuberculosis; however, the precise mechanism through which CS exposure facilitates Mycobacterium tuberculosis (Mtb) infection is unclear. We speculate that macrophage exposure to CS deregulates the cell death pathways that could explain, at least in part, the association observed between exposure to CS and pulmonary tuberculosis. We therefore established an in vitro model in which macrophages were exposed to CS and then infected with Mtb. Expression of surface markers was analyzed by flow cytometry, JNK1/2, ASK1, caspase 9, P-p38, Bcl-2 and Mcl-1 were analyzed by Western blot, and cytokines by ELISA. Our results show that exposure to CS limits macrophage ability to control Mtb growth. Moreover, this exposure reduced the expression of TLR2, Bcl-2 and Mcl-1, but increased that of JNK1 and ASK1 molecules in the macrophages. Finally, when the pre-exposed macrophages were infected with Mtb, the concentrations of TNFα, IL-1β and caspase-9 expression increased. This pro-inflammatory profile of the macrophage unbalanced the apoptosis/necrosis pathway. Taken together, these data suggest that macrophages exposed to CS are sensitized to cell death by MAPK kinase-dependent signaling pathway. Secretion of TNF-α and IL-1β by Mtb-infected macrophages promotes necrosis, and this deregulation of cell death pathways may favor the release of viable bacilli, thus leading to the progression of tuberculosis.
authors.affiliation: Laboratory of Integrative Immunology, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico.
authors.forename: Leslie
authors.initials: L
authors.lastname: Chávez-Galán
authors.forename: Lucero A
authors.initials: LA
authors.lastname: Ramon-Luing
authors.forename: Luis
authors.initials: L
authors.lastname: Torre-Bouscoulet
authors.forename: Rogelio
authors.initials: R
authors.lastname: Pérez-Padilla
authors.forename: Isabel
authors.initials: I
authors.lastname: Sada-Ovalle
mesh_terms: D017209:Apoptosis / Q000235:genetics; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism / Q000382:microbiology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009336:Necrosis / Q000382:microbiology; D012822:Silicon Dioxide / Q000009:adverse effects*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051195:Toll-Like Receptor 2; D012822:Silicon Dioxide; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; D053453:Caspase 9