{"doi":"10.17615/jgqs-nh87","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 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.","journal":"UNC Libraries","year":2024,"id":499891,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1348358,"name":"Ting J.P.-Y","orcid":null,"position":1,"is_corresponding":false},{"id":1349393,"name":"Batty C.J","orcid":null,"position":2,"is_corresponding":false},{"id":1349394,"name":"Gallovic M.D","orcid":null,"position":3,"is_corresponding":false},{"id":1349395,"name":"Ainslie K.M","orcid":null,"position":4,"is_corresponding":false},{"id":541000,"name":"Meng Deng","orcid":"0000-0002-9051-7534","position":5,"is_corresponding":false},{"id":1349396,"name":"Tam W","orcid":null,"position":6,"is_corresponding":false},{"id":482724,"name":"James C. Williams","orcid":"0000-0001-6665-6596","position":7,"is_corresponding":false},{"id":1349397,"name":"Matsushima G.K","orcid":null,"position":8,"is_corresponding":false},{"id":1349398,"name":"Bachelder E.M","orcid":null,"position":9,"is_corresponding":false},{"id":1349399,"name":"M. Thamilarasan","orcid":null,"position":10,"is_corresponding":false},{"id":1348981,"name":"Chou W.-C","orcid":null,"position":11,"is_corresponding":false},{"id":1349400,"name":"J M","orcid":null,"position":12,"is_corresponding":false},{"id":1349401,"name":"Gibson S.A","orcid":null,"position":13,"is_corresponding":false},{"id":1349040,"name":"Tomohiro Uchimura","orcid":"0000-0003-4816-6328","position":14,"is_corresponding":false},{"id":593313,"name":"Silva Markovic‐Plese","orcid":"0000-0002-0061-2707","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:10:04.829419Z","pmid":null,"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":[]}