2. Academic Validation
  3. STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN-Dependent and -Independent Immune-Regulatory Pathways

STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN-Dependent and -Independent Immune-Regulatory Pathways

  • J Immunol. 2021 May 1;206(9):2015-2028. doi: 10.4049/jimmunol.2001317.
Brandon M Johnson 1,  Toru Uchimura 1,  Matthew D Gallovic 2,  Madhan Thamilarasan 3,  Wei-Chun Chou 1,  Sara A Gibson 1,  Meng Deng 1 4,  Jason W Tam 1,  Cole J Batty 2,  Jonathan Williams 2,  Glenn K Matsushima 5,  Eric M Bachelder 2,  Kristy M Ainslie 2,  Silva Markovic-Plese 3,  Jenny P-Y Ting 6 5 7 8 9
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
  • 2 Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
  • 3 Department of Neurology, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
  • 4 Oral and Craniofacial Biomedicine Program, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
  • 5 Neuroscience Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
  • 6 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC; [email protected].
  • 7 Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
  • 8 Center for Translational Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and.
  • 9 Institute for Inflammatory Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
PMID: 33820855 DOI: 10.4049/jimmunol.2001317
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.

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