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Antagonism of the STING Pathway via Activation of the AIM2 Inflammasome by Intracellular DNA.


ABSTRACT: Recent evidence has indicated that innate immune sensing of cytosolic DNA in dendritic cells via the host STING pathway is a major mechanism leading to spontaneous T cell responses against tumors. However, the impact of the other major pathway triggered by intracellular DNA, the absent in melanoma 2 (AIM2) inflammasome, on the functional output from the stimulator of IFN genes (STING) pathway is poorly understood. We found that dendritic cells and macrophages deficient in AIM2, apoptosis-associated specklike protein, or caspase-1 produced markedly higher IFN-? in response to DNA. Biochemical analyses showed enhanced generation of cyclic GMP-AMP, STING aggregation, and TANK-binding kinase 1 and IFN regulatory factor 3 phosphorylation in inflammasome-deficient cells. Induction of pyroptosis by the AIM2 inflammasome was a major component of this effect, and inhibition of caspase-1 reduced cell death, augmenting phosphorylation of TANK-binding kinase 1/IFN regulatory factor 3 and production of IFN-?. Our data suggest that in vitro activation of the AIM2 inflammasome in murine macrophages and dendritic cells leads to reduced activation of the STING pathway, in part through promoting caspase-1-dependent cell death.

SUBMITTER: Corrales L 

PROVIDER: S-EPMC4800192 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Antagonism of the STING Pathway via Activation of the AIM2 Inflammasome by Intracellular DNA.

Corrales Leticia L   Woo Seng-Ryong SR   Williams Jason B JB   McWhirter Sarah M SM   Dubensky Thomas W TW   Gajewski Thomas F TF  

Journal of immunology (Baltimore, Md. : 1950) 20160229 7


Recent evidence has indicated that innate immune sensing of cytosolic DNA in dendritic cells via the host STING pathway is a major mechanism leading to spontaneous T cell responses against tumors. However, the impact of the other major pathway triggered by intracellular DNA, the absent in melanoma 2 (AIM2) inflammasome, on the functional output from the stimulator of IFN genes (STING) pathway is poorly understood. We found that dendritic cells and macrophages deficient in AIM2, apoptosis-associa  ...[more]

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