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IRF8 Regulates Gram-Negative Bacteria-Mediated NLRP3 Inflammasome Activation and Cell Death.


ABSTRACT: Inflammasomes are intracellular signaling complexes that are assembled in response to a variety of pathogenic or physiologic stimuli to initiate inflammatory responses. Ubiquitously present LPS in Gram-negative bacteria induces NLRP3 inflammasome activation that requires caspase-11. We have recently demonstrated that IFN regulatory factor (IRF) 8 was dispensable for caspase-11-mediated NLRP3 inflammasome activation during LPS transfection; however, its role in Gram-negative bacteria-mediated NLRP3 inflammasome activation remains unknown. In this study, we found that IRF8 promotes NLRP3 inflammasome activation in murine bone marrow-derived macrophages (BMDMs) infected with Gram-negative bacteria such as Citrobacter rodentium, Escherichia coli, or Pseudomonas aeruginosa mutant strain ?popB Moreover, BMDMs deficient in IRF8 showed substantially reduced caspase-11 activation and gasdermin D cleavage, which are required for NLRP3 inflammasome activation. Mechanistically, IRF8-mediated phosphorylation of IRF3 was required for Ifnb transcription, which in turn triggered the caspase-11-dependent NLRP3 inflammasome activation in the infected BMDMs. Overall, our findings suggest that IRF8 promotes NLRP3 inflammasome activation during infection with Gram-negative bacteria.

SUBMITTER: Karki R 

PROVIDER: S-EPMC7291389 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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IRF8 Regulates Gram-Negative Bacteria-Mediated NLRP3 Inflammasome Activation and Cell Death.

Karki Rajendra R   Lee Ein E   Sharma Bhesh R BR   Banoth Balaji B   Kanneganti Thirumala-Devi TD  

Journal of immunology (Baltimore, Md. : 1950) 20200323 9


Inflammasomes are intracellular signaling complexes that are assembled in response to a variety of pathogenic or physiologic stimuli to initiate inflammatory responses. Ubiquitously present LPS in Gram-negative bacteria induces NLRP3 inflammasome activation that requires caspase-11. We have recently demonstrated that IFN regulatory factor (IRF) 8 was dispensable for caspase-11-mediated NLRP3 inflammasome activation during LPS transfection; however, its role in Gram-negative bacteria-mediated NLR  ...[more]

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