STING manifests self DNA-dependent inflammatory disease

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.

DNase II-dependent DNA digestion is required for DNA sensing by TLR9

“…In the absence of DNase II, the STING pathway is constitutively activated 15 , whereas TLR9 activation was found to be impaired as found in this study. Engulfed apoptotic DNA in the lysosomes is likely to leak into the cytoplasm and activate the STING pathway.…”

“…In this regard, it is of note that cytoplasmic DNA sensors rather than endosomal TLR9 are activated in Dnase2a À / À mice. IFN-b-dependent lethality and chronic arthritis are not found in mice lacking both DNase II and STING 15 . Even though endogenous DNA accumulates in lysosomes in Dnase2a À / À mice, TLR9 is not required for IFN-b production 16 .…”

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

“…Next to TREX1-associated disorders, STING deficiency has also been reported to rescue from lethal inflammation in the context of another disease model, in which endogenous DNA is erroneously sensed by the innate immune system (22). Mice lacking DNase II show a dramatic STING-dependent type I IFN response because of the fact that DNA within the lysosomal compartment of phagocytic cells fails to be degraded and subsequently translocates into the cytoplasm (23).…”

Innate immune signaling and regulation in cancer immunotherapy

“…In particular, inappropriate activation of the STING pathway and generation of type I IFNs could promote the Aicardi-Goutières syndrome [75] or systemic lupus erythematosus [76]. Several mechanisms for negative regulation of the STING pathway have been described, such as elimination of accumulated DNA by DNases [77] and post-translational modification of proteins in the pathway after stimulation [78]. Recent work has indicated another level of regulation, which is dual stimulation of two innate immune pathways by the same ligand having opposing functional consequences.…”