1. STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN-Dependent and -Independent Immune-Regulatory Pathways.
- Author
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Johnson, Brandon M., Toru Uchimura, Gallovic, Matthew D., Thamilarasan, Madhan, Wei-Chun Chou, Gibson, Sara A., Meng Deng, Tam, Jason W., Batty, Cole J., Williams, Jonathan, Matsushima, Glenn K., Bachelder, Eric M., Ainslie, Kristy M., Markovic-Plese, Silva, and Ting, Jenny P.-Y.
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ENCEPHALOMYELITIS , *DISEASE relapse , *MULTIPLE sclerosis , *CANCER vaccines , *AUTOIMMUNE diseases , *CD25 antigen - Abstract
The cGAS-cyclic GMP-AMP (cGAMP)-stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immune-regulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing-remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor' STING. We used microparticle (MP)-encapsulated cGAMP to increase cellular delivery' achieve dose sparing' and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion' whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing-remitting model. Importantly' cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-β. Mechanistically, cGAMP MPs showed both IFN-I-dependent and -independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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