Antagonism of the STING pathway via activation of the AIM2 inflammasome by intracellular DNA

L Corrales, SR Woo, JB Williams… - The Journal of …, 2016 - journals.aai.org
L Corrales, SR Woo, JB Williams, SM McWhirter, TW Dubensky, TF Gajewski
The Journal of Immunology, 2016journals.aai.org
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 …
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-β 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-β. 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.
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