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.