title: Intrinsic self-DNA triggers inflammatory disease dependent on STING.
abstract: Inflammatory diseases such as Aicardi-Goutières syndrome and severe systemic lupus erythematosus are generally lethal disorders that have been traced to defects in the exonuclease TREX1 (DNase III). Mice lacking TREX1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the stimulator of IFN genes (STING) pathway. In this study, we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into TREX1(-/-) mice. TREX1(-/-) macrophages did not exhibit significant augmented ability to produce proinflammatory cytokines compared with normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies.
authors.affiliation: Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; and.
authors.forename: Jeonghyun
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136.
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.affiliation: Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; and gbarber@med.miami.edu.
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D005090:Exodeoxyribonucleases; D018836:Inflammation Mediators; D008565:Membrane Proteins; D010750:Phosphoproteins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C429526:three prime repair exonuclease 1