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Caspases-1 and caspase-11 mediate pyroptosis, inflammation, and control of Brucella joint infection.

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 investigated the role of inflammasomes and their effectors, including IL-1, IL-18 and pyroptosis, on inflammation and control of infection during Brucella-induced arthritis. Early in infection, both caspase-1 and caspase-11 were found to initiate joint inflammation and pro-inflammatory cytokine production. However, by one week post-infection caspase-1 and caspase-11 also contributed to control of Brucella joint infection. Inflammasome dependent restriction of Brucella joint burdens did not require AIM2 or NLRP3. IL-1R had a modest effect on Brucella-induced joint swelling, but mice lacking IL-1R were not impaired in their ability to control infection of the joint by Brucella In contrast, IL-18 contributed to the initiation of joint swelling and control of joint Brucella infection. Caspase1/11-dependent cell death was observed in vivo, and in vitro studies demonstrated caspase-1 and caspase-11 both induce pyroptosis which limited Brucella infection in macrophages. Brucella LPS alone was also able to induce caspase-11 dependent pyroptosis. Collectively these data demonstrate inflammasomes induce inflammation in an IL-18 dependent manner, and inflammasome-dependent IL-18 and pyroptosis restrict Brucella infection.

SUBMITTER: Lacey CA

PROVIDER: S-EPMC6105886 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Caspase-1 and Caspase-11 Mediate Pyroptosis, Inflammation, and Control of Brucella Joint Infection.

Lacey Carolyn A CA Mitchell William J WJ Dadelahi Alexis S AS Skyberg Jerod A JA

Infection and immunity 20180822 9

Brucellosis, caused by the intracellular bacterial pathogen <i>Brucella</i>, is a zoonotic disease for which arthritis is the most common focal complication in humans. Here we investigated the role of inflammasomes and their effectors, including interleukin-1 (IL-1), IL-18, and pyroptosis, on inflammation and control of infection during <i>Brucella</i>-induced arthritis. Early in infection, both caspase-1 and caspase-11 were found to initiate joint inflammation and proinflammatory cytokine produ ...[more]

PMID: 29941463

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Project description:Infection with Burkholderia pseudomallei or B. thailandensis triggers activation of the NLRP3 and NLRC4 inflammasomes leading to release of IL-1β and IL-18 and death of infected macrophages by pyroptosis, respectively. The non-canonical inflammasome composed of caspase-11 is also activated by these bacteria and provides protection through induction of pyroptosis. The recent generation of bona fide caspase-1-deficient mice allowed us to reexamine in a mouse model of pneumonic melioidosis the role of caspase-1 independently of caspase-11 (that was also absent in previously generated Casp1-/- mice). Mice lacking either caspase-1 or caspase-11 were significantly more susceptible than wild type mice to intranasal infection with B. thailandensis. Absence of caspase-1 completely abolished production of IL-1β and IL-18 as well as pyroptosis of infected macrophages. In contrast, in mice lacking caspase-11 IL-1β and IL-18 were produced at normal level and macrophages pyroptosis was only marginally affected. Adoptive transfer of bone marrow indicated that caspase-11 exerted its protective action both in myeloid cells and in radio-resistant cell types. B. thailandensis was shown to readily infect mouse lung epithelial cells triggering pyroptosis in a caspase-11-dependent way in vitro and in vivo. Importantly, we show that lung epithelial cells do not express inflammasomes components or caspase-1 suggesting that this cell type relies exclusively on caspase-11 for undergoing cell death in response to bacterial infection. Finally, we show that IL-18's protective action in melioidosis was completely dependent on its ability to induce IFNγ production. In turn, protection conferred by IFNγ against melioidosis was dependent on generation of ROS through the NADPH oxidase but independent of induction of caspase-11. Altogether, our results identify two non-redundant protective roles for caspase-1 and caspase-11 in melioidosis: Caspase-1 primarily controls pyroptosis of infected macrophages and production of IL-18. In contrast, caspase-11 mediates pyroptosis of infected lung epithelial cells.

Dataset Information

Caspases-1 and caspase-11 mediate pyroptosis, inflammation, and control of Brucella joint infection.

Publications

Caspase-1 and Caspase-11 Mediate Pyroptosis, Inflammation, and Control of Brucella Joint Infection.

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