title: Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β.
abstract: Interleukin 1 (IL-1) is an important mediator of innate immunity but can also promote inflammatory tissue damage. During chronic infections such as tuberculosis, the beneficial antimicrobial role of IL-1 must be balanced with the need to prevent immunopathology. By exogenously controlling the replication of Mycobacterium tuberculosis in vivo, we obviated the requirement for antimicrobial immunity and discovered that both IL-1 production and infection-induced immunopathology were suppressed by lymphocyte-derived interferon-γ (IFN-γ). This effect was mediated by nitric oxide (NO), which we found specifically inhibited assembly of the NLRP3 inflammasome via thiol nitrosylation. Our data indicate that the NO produced as a result of adaptive immunity is indispensable in modulating the destructive innate inflammatory responses elicited during persistent infections.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Bibhuti B
authors.initials: BB
authors.lastname: Mishra
authors.forename: Vijay A K
authors.initials: VA
authors.lastname: Rathinam
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Martens
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Martinot
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sassetti
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D046188:Protein Modification, Translational / Q000235:genetics / Q000276:immunology; D055503:Protein Multimerization / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009569:Nitric Oxide; D007371:Interferon-gamma