title: Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis.
abstract: As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1β in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulence-associated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1β in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1-dependent manner. However, during TB, MTB promotes NLRP3- and caspase-1-independent IL-1β release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models.
authors.affiliation: Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Anca
authors.initials: A
authors.lastname: Dorhoi
authors.forename: Geraldine
authors.initials: G
authors.lastname: Nouailles
authors.forename: Sabine
authors.initials: S
authors.lastname: Jörg
authors.forename: Kristine
authors.initials: K
authors.lastname: Hagens
authors.forename: Ellen
authors.initials: E
authors.lastname: Heinemann
authors.forename: Lydia
authors.initials: L
authors.lastname: Pradl
authors.forename: Dagmar
authors.initials: D
authors.lastname: Oberbeck-Müller
authors.forename: Maria Adelaida
authors.initials: MA
authors.lastname: Duque-Correa
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Reece
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Olaf
authors.initials: O
authors.lastname: Gross
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004198:Disease Susceptibility; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000503:physiopathology; D014613:Vaccines, Attenuated; D014774:Virulence
chemical_list: D002352:Carrier Proteins; C107475:Esx1 protein, mouse; D018398:Homeodomain Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014613:Vaccines, Attenuated