title: Borrelia species induce inflammasome activation and IL-17 production through a caspase-1-dependent mechanism.
abstract: Borrelia burgdorferi spirochetes cause Lyme disease, which can result in severe clinical symptoms such as multiple joint inflammation and neurological disorders. IFN-γ and IL-17 have been suggested to play an important role in the host defense against Borrelia, and in the immunopathology of Lyme disease. The caspase-1-dependent cytokine IL-1β has been linked to the generation of IL-17-producing T cells, whereas caspase-1-mediated IL-18 is crucial for IFN-γ production. In this study, we show by using knockout mice the role of inflammasome-activated caspase-1 in the regulation of cytokine responses by B. burgdorferi. Caspase-1-deficient cells showed significantly less IFN-γ and IL-17 production after Borrelia stimulation. A lack of IL-1β was responsible for the defective IL-17 production, whereas IL-18 was crucial for the IFN-γ production. Caspase-1-dependent IL-33 played no role in the Borrelia-induced production of IL-1β, IFN-γ or IL-17. In conclusion, we describe for the first time the role of the inflammasome-dependent caspase-1 activation of cytokines in the regulation of IL-17 production induced by Borrelia spp. As IL-17 has been implicated in the pathogenesis of chronic Lyme disease, these data suggest that caspase-1 targeting may represent a new immunomodulatory strategy for the treatment of complications of late stage Lyme disease.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Patrick
authors.initials: P
authors.lastname: Sturm
authors.forename: Ineke
authors.initials: I
authors.lastname: Verschueren
authors.forename: Anneleen
authors.initials: A
authors.lastname: Berende
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
mesh_terms: D000818:Animals; D001898:Borrelia / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D053583:Interleukin-1beta / Q000172:deficiency / Q000276:immunology; D008193:Lyme Disease / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D020381:Interleukin-17; D053583:Interleukin-1beta; D020170:Caspase 1