title: 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-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.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637;
authors.forename: Leticia
authors.identifier: http://orcid.org/0000-0002-2800-4156
authors.initials: L
authors.lastname: Corrales
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637;
authors.forename: Seng-Ryong
authors.identifier: http://orcid.org/0000-0002-4843-5113
authors.initials: SR
authors.lastname: Woo
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637;
authors.forename: Jason B
authors.identifier: http://orcid.org/0000-0001-7123-6940
authors.initials: JB
authors.lastname: Williams
authors.affiliation: Aduro Biotech, Berkeley, CA 94710; and.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: McWhirter
authors.affiliation: Aduro Biotech, Berkeley, CA 94710; and.
authors.forename: Thomas W
authors.identifier: http://orcid.org/0000-0003-0726-4597
authors.initials: TW
authors.lastname: Dubensky
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637; Section of Hematology/Oncology 2, Department of Medicine, The University of Chicago, Chicago, IL 60637 tgajewsk@medicine.bsd.uchicago.edu.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D004247:DNA / Q000276:immunology* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D058847:Inflammasomes; D007371:Interferon-gamma / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000378:metabolism; D000069292:Pyroptosis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D020170:Caspase 1; D004247:DNA; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D007371:Interferon-gamma; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C540422:Aim2 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase