title: Activation of the STING adaptor attenuates experimental autoimmune encephalitis.
abstract: Cytosolic DNA sensing activates the stimulator of IFN genes (STING) adaptor to induce IFN type I (IFN-αβ) production. Constitutive DNA sensing to induce sustained STING activation incites tolerance breakdown, leading to autoimmunity. In this study, we show that systemic treatments with DNA nanoparticles (DNPs) induced potent immune regulatory responses via STING signaling that suppressed experimental autoimmune encephalitis (EAE) when administered to mice after immunization with myelin oligodendrocyte glycoprotein (MOG), at EAE onset, or at peak disease severity. DNP treatments attenuated infiltration of effector T cells into the CNS and suppressed innate and adaptive immune responses to myelin oligodendrocyte glycoprotein immunization in spleen. Therapeutic responses were not observed in mice treated with cargo DNA or cationic polymers alone, indicating that DNP uptake and cargo DNA sensing by cells with regulatory functions was essential for therapeutic responses to manifest. Intact STING and IFN-αβ receptor genes, but not IFN-γ receptor genes, were essential for therapeutic responses to DNPs to manifest. Treatments with cyclic diguanylate monophosphate to activate STING also delayed EAE onset and reduced disease severity. Therapeutic responses to DNPs were critically dependent on IDO enzyme activity in hematopoietic cells. Thus, DNPs and cyclic diguanylate monophosphate attenuate EAE by inducing dominant T cell regulatory responses via the STING/IFN-αβ/IDO pathway that suppress CNS-specific autoimmunity. These findings reveal dichotomous roles for the STING/IFN-αβ pathway in either stimulating or suppressing autoimmunity and identify STING-activating reagents as a novel class of immune modulatory drugs.
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Henrique
authors.initials: H
authors.lastname: Lemos
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Chandler
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Eslam
authors.initials: E
authors.lastname: Mohamed
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912; Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP 14049-900 Sao Paulo, Brazil;
authors.forename: Guilherme R
authors.initials: GR
authors.lastname: Souza
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Lingqian
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Pacholczyk
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136; and.
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.affiliation: Department of Applied Chemistry, Faculty of Engineering, Aichi Institute of Technology, Toyota 470-0392, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912; amellor@gru.edu.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007108:Immune Tolerance / Q000235:genetics; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology; D007372:Interferons / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D000099197:STING Protein
chemical_list: D004247:DNA; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007372:Interferons; D008565:Membrane Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D017471:Receptors, Interferon; C571327:Mog protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein