{"doi":"10.4049/jimmunol.2001317","title":"STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN–Dependent and –Independent Immune-Regulatory Pathways","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.","journal":"The Journal of Immunology","year":2021,"id":166660,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":692526,"name":"Toru Uchimura","orcid":"0009-0000-7057-2475","position":1,"is_corresponding":false},{"id":693215,"name":"Matthew D. Gallovic","orcid":null,"position":2,"is_corresponding":false},{"id":510249,"name":"Madhan Thamilarasan","orcid":"0000-0003-3740-0852","position":3,"is_corresponding":false},{"id":225640,"name":"Wei-Chun Chou","orcid":"0000-0003-2006-5568","position":4,"is_corresponding":false},{"id":300389,"name":"Sara A. Gibson","orcid":null,"position":5,"is_corresponding":false},{"id":541000,"name":"Meng Deng","orcid":"0000-0002-9051-7534","position":6,"is_corresponding":false},{"id":225643,"name":"Jason W. Tam","orcid":"0000-0003-3659-5088","position":7,"is_corresponding":false},{"id":463638,"name":"Cole J. Batty","orcid":"0000-0002-5631-2623","position":8,"is_corresponding":false},{"id":693216,"name":"Jonathan W. Williams","orcid":null,"position":9,"is_corresponding":false},{"id":219937,"name":"Glenn K. Matsushima","orcid":null,"position":10,"is_corresponding":false},{"id":419622,"name":"Eric M. Bachelder","orcid":"0000-0002-8572-888X","position":11,"is_corresponding":false},{"id":419623,"name":"Kristy M. Ainslie","orcid":"0000-0002-1820-8382","position":12,"is_corresponding":false},{"id":593313,"name":"Silva Markovic‐Plese","orcid":"0000-0002-0061-2707","position":13,"is_corresponding":false},{"id":299129,"name":"Jenny P.‐Y. Ting","orcid":"0000-0002-7846-0395","position":14,"is_corresponding":false},{"id":598685,"name":"Brandon M. Johnson","orcid":"0000-0002-3871-3378","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:45:49.644768Z","pmid":"33820855","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}