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- W4313359547 abstract "Abstract Brucellosis, caused by the intracellular bacterial pathogen Brucella, is a zoonotic disease for which arthritis is the most common focal complication in humans. Here we show caspase-1 (casp1) and caspase-11 (casp11) initiate Brucella-induced joint inflammation, but later in infection also restrict Brucella replication. In contrast, AIM2 and NLRP3 were dispensable for control of joint infection by Brucella. Both IL-1 and IL-18 promoted joint inflammation, however only IL-18 contributed to protection against Brucella infection of the joint. In vitro studies demonstrated that casp1 and casp11 both induce pyroptosis which limited Brucella infection in macrophages. While IFN-γ production in part required casp1/11 and IL-18, casp1/11-dependent clearance of Brucella was only partially IFN-γ dependent. However, IFN-γ deficiency resulted in severe inflammation that was entirely inflammasome dependent, and in particular reliant on NLRP3. IFN-γ was vital for induction of the nitric oxide (NO) producing enzyme, iNOS, in infected joints, and NO inhibited casp1 activation in Brucella-infected macrophages in vitro. During Brucella infection in vivo, iNOS inhibition exacerbated arthritis, and administration of a NO donor reduced joint inflammation in IFN-γ-deficient mice. Collectively these data demonstrate inflammasomes induce early inflammation in an IL-18 and IL-1 dependent manner, and inflammasome-dependent IL-18 and pyroptosis restrict Brucella burdens in the joint. Moreover, IFN-γ reduces inflammation by inhibiting excessive casp1 activation through production of NO. Thus NO donors, in combination with antibiotics, may be an effective therapy for treating Brucella-induced inflammation." @default.
- W4313359547 created "2023-01-06" @default.
- W4313359547 creator A5009868743 @default.
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- W4313359547 date "2018-05-01" @default.
- W4313359547 modified "2023-09-27" @default.
- W4313359547 title "Inflammasomes confer protection via IL-18 and pyroptosis, and are negatively regulated by IFN-γ-dependent nitric oxide during <i>Brucella</i> infection" @default.
- W4313359547 doi "https://doi.org/10.4049/jimmunol.200.supp.115.11" @default.
- W4313359547 hasPublicationYear "2018" @default.
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