Autoimmune diseases such as systemic lupus erythematosus (SLE) affect millions worldwide, the cause of which remains unknown. SLE and diseases such as Aicardi-Goutieres syndrome (AGS) are characterized by the overproduction of cytokines such as type I interferon (IFN), speculatively by chronic infection or self nucleic acids. Mice lacking DNAse II die during embryonic development through comparable autoimmune disease since phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensors are activated resulting in the production of a variety of cytokines including type I IFN. The cellular sensor responsible for triggering DNA-mediated inflammation aggravated autoimmune disease remains to be determined. However, we report here that STING (Stimulator of Interferon Genes) complexes with phagocytosed undigested DNA and controls innate immune signaling events that facilitate such events. DNase II-dependent autoimmune embryonic lethality was rescued by loss of STING function and polyarthritis completely prevented since cytosolic DNA failed to trigger cytokine production. Accordingly, loss of STING similarly alleviated Trex1-dependent lethal inflammatory myocarditis in mice, a model for AGS. Our data provides molecular insight into the causes of DNA-mediated inflammation-dependent autoimmune disorders and affords a new target that could plausibly be therapeutically controlled, to help prevent such diseases.
- Copyright © 2013 by The American Association of Immunologists, Inc.