In systemic lupus erythematosus (SLE), the most common form of lupus, elevated levels of type I interferon (IFN-I) and IFN-I-stimulated genes (ISGs) are found in the serum of peripheral blood. Clinical trials that target IFN-I have revealed that such therapies are more effective when patients also have high ISG expression.
However, how exactly IFN-I is produced that leads to progression of SLE remains unclear. New findings published in the Annals of the Rheumatic Diseases investigate this underlying mechanism, particularly in terms of the involvement of the enzyme cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE.
"To address this issue, we used patient samples and a cell-based reporter system that enables highly sensitive measurement of serum IFN-I bioactivity and ISG-inducing activity,” explained study first co-author Yasuhiro Kato. Kato comes from a team led by Osaka University in Japan. The team’s reporter system involved reporter cells that featured knockouts of cGAS, STING and IFNAR2 to evaluate signaling pathway-dependent ISG induction.
In their results, the team found that that the ISG-inducing activity of SLE sera was significantly reduced in STING-knockout reporter cells, and STING-dependent ISG-inducing activity correlated with disease activity. Apoptosis-derived membrane vesicles (AdMVs)--which have high ISG-inducing activity--were also reduced in cGAS-knockout or STING-knockout reporter cells. These results highlight the key role of the cGAS-STING pathway.
Finally, the team also detected elevated levels of double-stranded DNA, which is known to trigger an IFN-I overproduction pathway. This leads the team to propose a model of SLE pathophysiology: Apoptotic cells release AdMVs containing dsDNA, which in turn activates the cGAS-STING pathway. Production of IFN-I from this pathway can then activate other immune cells, such as B and T lymphocytes, and promote secretion of autoantibodies that cause tissue damage.
“We showed that SLE serum induced ISGs, in part, through cGAS-STING pathway, a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes," said Kato.
The team concludes in their paper: “Thus, blockade of the cGAS–STING axis represents a promising therapeutic target for SLE. Moreover, our cell-based reporter system may be useful for stratifying patients with SLE with high ISG-inducing activity.”
Image: Model of recurrent type I IFN production in SLE patients. Image courtesy of Osaka University.