RRC ID 19139
Author Ahn J, Gutman D, Saijo S, Barber GN.
Title STING manifests self DNA-dependent inflammatory disease.
Journal Proc. Natl. Acad. Sci. U.S.A.
Abstract Inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and polyarthritis are characterized by chronic cytokine overproduction, suggesting that the stimulation of host innate immune responses, speculatively by persistent infection or self nucleic acids, plays a role in the manifestation of these disorders. Mice lacking DNase II die during embryonic development through comparable inflammatory disease because phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensor pathways are engaged, resulting in the production of a variety of cytokines including type I IFN. The cellular sensor pathway(s) responsible for triggering DNA-mediated inflammation aggravated autoimmune disease remains to be determined. However, we report here that Stimulator of IFN Genes (STING) is responsible for inflammation-related embryonic death in DNase II defective mice initiated by self DNA. DNase II-dependent embryonic lethality was rescued by loss of STING function, and polyarthritis completely prevented because cytosolic DNA failed to robustly trigger cytokine production through STING-controlled signaling pathways. Our data provides significant molecular insight into the causes of DNA-mediated inflammatory disorders and affords a target that could plausibly be therapeutically controlled to help prevent such diseases.
Volume 109(47)
Pages 19386-91
Published 2012-11-20
DOI 10.1073/pnas.1215006109
PII 1215006109
PMID 23132945
PMC PMC3511090
MeSH Aging / genetics Aging / pathology Animals Apoptosis Arthritis / immunology Arthritis / pathology Cytokines / biosynthesis DNA / immunology* Embryo Loss / genetics Embryo Loss / immunology Embryo, Mammalian / metabolism Endodeoxyribonucleases / deficiency Endodeoxyribonucleases / metabolism Gene Expression Regulation, Developmental Inflammation / immunology* Inflammation / pathology* Membrane Proteins / deficiency Membrane Proteins / metabolism* Mice Mice, Knockout Necrosis
IF 9.58
Times Cited 126
Mice DNase II Hetero Knockout mouse (RBRC01725)