ID: 177: Pathogen recognition and STING signaling

Abstract

We have recently reported that STING (stimulator of interferon genes) is essential for controlling Toll-Like Receptor (TLR)-independent, cytosolic DNA-mediated innate immune signaling. Accordingly, STING appears essential for protecting the host against lethal disease following infection by pathogens such as HSV1. Such cellular DNA sensors may also play a key role in triggering inflammation aggravated autoimmune diseases. Autoimmune diseases such as Aicardi-Goutieres syndrome (AGS) are characterized by the overproduction of cytokines such as type I interferon (IFN) suggesting that stimulation of host innate immune responses, speculatively by chronic infection or self-nucleic acids, play a role in the manifestation of these diseases. It is known that mice lacking DNAse II die during embryonic development through comparable inflammatory 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. However, we have found that STING 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 robustly trigger cytokine production through STING controlled signaling pathways. Consequently, loss of STING expression similarly alleviated Trex-1-dependent lethal inflammatory myocarditis is mice, a model for AGS, speculatively caused by endogenous self DNA. Our data provides molecular insight into the causes of DNA-mediated inflammation-dependent autoimmune disorders as well as inflammation driven cancer and affords a new target that could plausibly be therapeutically controlled, to help prevent such diseases.