A little STING could go a long way in helping treat or even avoid autoimmune diseases such as arthritis, type 1 diabetes and multiple sclerosis, researchers report.
With some prompting, the protein STING can turn down the immune response or even block its attack on healthy body constituents like collagen, insulin and the protective covering of neurons, all targets in these debilitating diseases, said Dr. Andrew L. Mellor, immunologist at the Medical College of Georgia at Georgia Regents University.
MCG researchers saw STING's critical role play out after they injected into the bloodstream submicroscopic DNA nanoparticles, engineered carriers for delivering drugs or genes into cells. Last year, the researchers were the first to report that even empty-handed, these DNA nanoparticles could suppress immunity by evoking expression of the enzyme IDO in a mouse model of arthritis.
Now they learn that the magic is in STING, which recognizes the molecule that senses the DNA then prompts release of IDO, or indoleomine 2,3-dioxyegenase.
"The fact that STING is actually part of the DNA-sensing pathway tells us something we did not know before," said Mellor, corresponding author of the study in the rapid publication section of the Journal of Immunology.
In fact, mice without STING, had no response to the DNA nanoparticle, the researchers report.
DNA nanoparticles apparently look to the body a lot like the debris that results when dying cells release DNA from their nucleus. "You could draw the analogy that DNA nanoparticles are perhaps mimicking what happens when cells die in certain ways," Mellor said. Researchers already knew there was a link between STING and immunity: the food-borne bacterium listeria releases cyclic dinucleotides to activate STING in cells it has infected. However it's the first time they realized that in this case and others, STING actually turns the immune system off. "Obviously this is one way that the bacterium may avoid being eliminated," Mellor said. He believes STING can do the same for the collagen in knee cartilage and much more.
One question is the best way to activate STING. Mellor's recently awarded $1.4 million grant from the National Institutes of Health should help answer that and more. Researchers will be comparing results from STING's activation by DNA nanoparticles to its more direct stimulation by cyclic dinucleotides. "Think of it as a surrogate for DNA," Mellor said of cyclic dinucleotide, which has a lot of appeal because it's easy to synthesize and its direct effect may reduce the side effect potential. "We need to know which is the best approach in disease," Mellor said.
He's also pursuing his original premise by loading antigens for insulin and myelin - immune targets in type 1 diabetes and multiple sclerosis, respectively - onto the DNA nanoparticles to see if that enhances their therapeutic effect. He'll also further explore STING's response to DNA nanoparticles in these two disease models.