دورية أكاديمية
Sting agonist mitigates experimental autoimmune encephalomyelitis by stimulating type i ifn-dependent and -independent immune-regulatory pathways
| العنوان: | Sting agonist mitigates experimental autoimmune encephalomyelitis by stimulating type i ifn-dependent and -independent immune-regulatory pathways |
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| المؤلفون: | Johnson B.M, Uchimura T, Gallovic M.D, Thamilarasan M, Chou W.-C, Gibson S.A, Deng M, Tam J.W, Batty C.J, Williams J, Matsushima G.K, Bachelder E.M, Ainslie K.M, Markovic-Plese S, Ting J.P.-Y |
| المصدر: | Journal of Immunology, 206(9) |
| بيانات النشر: | American Association of Immunologists |
| سنة النشر: | 2021 |
| المجموعة: | Carolina Digital Repository (UNC - University of North Carolina) |
| مصطلحات موضوعية: | Membrane Proteins, histology, Sting1 protein, mouse, in vivo study, male, drug delivery system, knockout mouse, immunoblotting, real time reverse transcription polymerase chain reaction, CD4-Positive T-Lymphocytes, metabolism, Article, stimulator of interferon gene, cyclic AMP responsive element binding protein, immunosuppressive treatment, cyclic AMP, Encephalomyelitis, Autoimmune, Experimental, mononuclear cell, animal tissue, animal, Interferon Type I, Female, enzyme linked immunosorbent assay, T lymphocyte, peripheral blood mononuclear cell, Leukocytes, Mononuclear |
| الوصف: | 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 immuneregulatory 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-b. 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://doi.org/10.17615/jgqs-nh87Test; https://cdr.lib.unc.edu/downloads/sf268g74s?file=thumbnailTest; https://cdr.lib.unc.edu/downloads/sf268g74sTest |
| DOI: | 10.17615/jgqs-nh87 |
| الإتاحة: | https://doi.org/10.17615/jgqs-nh87Test https://cdr.lib.unc.edu/downloads/sf268g74s?file=thumbnailTest https://cdr.lib.unc.edu/downloads/sf268g74sTest |
| رقم الانضمام: | edsbas.BEBA158F |
| قاعدة البيانات: | BASE |
| DOI: | 10.17615/jgqs-nh87 |
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