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Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.

ABSTRACT: IFN receptor signaling induces cell-autonomous immunity to infections with intracellular bacterial pathogens. Here, we demonstrate that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11-dependent, cell-autonomous immunity in response to cytoplasmic LPS. Caspase-11-dependent pyroptosis is triggered in IFN-activated macrophages infected with the Gram-negative bacterial pathogen Legionella pneumophila. The rapid induction of pyroptosis in IFN-activated macrophages required a cluster of IFN-inducible Gbp proteins encoded on mouse chromosome 3 (Gbp(chr3)). Induction of pyroptosis in naive macrophages by infections with the cytosol-invading ΔsdhA L. pneumophila mutant was similarly dependent on Gbp(chr3), suggesting that these Gbp proteins play a role in the detection of bacteria accessing the cytosol. Cytoplasmic LPS derived from Salmonella ssp. or Escherichia coli has recently been shown to trigger caspase-11 activation and pyroptosis, but the cytoplasmic sensor for LPS and components of the caspase-11 inflammasome are not yet defined. We found that the induction of caspase-11-dependent pyroptosis by cytoplasmic L. pneumophila-derived LPS required Gbp(chr3) proteins. Similarly, pyroptosis induced by cytoplasmic LPS isolated from Salmonella was diminished in Gbp(chr3)-deficient macrophages. These data suggest a role for Gbp(chr3) proteins in the detection of cytoplasmic LPS and the activation of the noncanonical inflammasome.

SUBMITTER: Pilla DM

PROVIDER: S-EPMC4000848 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.

Pilla Danielle M DM Hagar Jon A JA Haldar Arun K AK Mason Ashley K AK Degrandi Daniel D Pfeffer Klaus K Ernst Robert K RK Yamamoto Masahiro M Miao Edward A EA Coers Jörn J

Proceedings of the National Academy of Sciences of the United States of America 20140408 16

IFN receptor signaling induces cell-autonomous immunity to infections with intracellular bacterial pathogens. Here, we demonstrate that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11-dependent, cell-autonomous immunity in response to cytoplasmic LPS. Caspase-11-dependent pyroptosis is triggered in IFN-activated macrophages infected with the Gram-negative bacterial pathogen Legionella pneumophila. The rapid induction of pyroptosis in IFN-activated macrophages required ...[more]

PMID: 24715728

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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.

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Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.

Publications

Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.

Similar Datasets

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