Activation of the STING Adaptor Attenuates Experimental Autoimmune Encephalitis

Abstract

Cytosolic DNA sensing activates the Stimulator of Interferon Genes (STING) adaptor to induce interferon type I (IFNαβ) production. Constitutive DNA sensing to induce sustained STING activation incites tolerance breakdown leading to autoimmunity. Here 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 central nervous system (CNS) and suppressed innate and adaptive immune responses to MOG 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 IFNαβ receptor genes, but not IFNγ receptor genes, were essential for therapeutic responses to DNPs to manifest. Treatments with cyclic diguanylate monophosphate (c-diGMP) to activate STING also delayed EAE onset and reduced disease severity. Therapeutic responses to DNPs were critically dependent on indoleamine 2,3 dioxygenase (IDO) enzyme activity in hematopoietic cells. Thus DNPs and c-diGMP attenuate EAE by inducing dominant T cell regulatory responses via the STING-IFNαβ-IDO pathway that suppress CNS-specific autoimmunity. These findings reveal dichotomous roles for the STING-IFNαβ pathway in either stimulating or suppressing autoimmunity and identify STING activating reagents as a novel class of immune modulatory drugs.

Suppression of systemic autoimmunity by the innate immune adaptor STING

“…6H). These data, along with other recent studies (29), explain how immune suppression in STING −/− animals may be systemically compromised. Overall, these data strongly indicate that in the context of an SLE autoimmune-prone background, STINGdeficient myeloid cells mount an amplified response to nucleic acid-associated autoantigens caused by the reduced expression of molecules that directly or indirectly limit immune activation.…”

Role of indoleamine 2,3-dioxygenase in health and disease

“…Also, administration of Kyn pathway metabolites (picolinic acid, QA, 3-HAA and 3-HK) or induction of IDO1 in DCs skews the EAE Th1 immune response towards a Th2/Treg response, reduces APC activation, induces cell cycle arrest of myelin-specific CD4 + T-cells and encourages myelin repair, resulting in milder relapses and substantially reduced disease severity [286,288,289]. Interestingly, the ability of disparate treatments, including pluripotent stem cells [288], DNA nanoparticles, cyclic dinucleotides (that activate the STING adaptor pathway) [290] and an oestrogen receptor agonist [291], to induce dominant Treg responses and protect against experimental EAE relates to their shared ability to induce IDO1.…”

“…Ido1 gene-knockout mice do not develop spontaneous autoimmune disorders, indicating that the enzyme's immunosuppressive action is not essential for the Table 1 Roles of IDO1 and the Kyn pathway in different physiological and disease settings in experimental animals NB: commonly studied experimental animal cancer models are detailed in Table 3 Murine syngenic pregnancy Not required [217] Colitis Murine trinitrobenzene sulfonic acid-induced colitis Protective [275,276,281,283] Murine dextran sodium sulfate-induced colitis Protective [276,282] Murine T-cell transfer colitis model Protective [282] Citrobacter rodentium-induced colitis in mice Harmful [44] Multiple sclerosis Murine experimental autoimmune encephalomyelitis Protective [121,284,286,[288][289][290][291] Lupus MRL lpr/lpr mice Protective [277] Autoimmune diabetes Non-obese diabetic mice Protective [127] STZ-induced diabetes mouse model Protective [292] Transplantation Pancreatic islet transplantation in an STZ-induced diabetes mouse model…”

Chemo-Immunotherapy: Role of Indoleamine 2,3-Dioxygenase in Defining Immunogenic Versus Tolerogenic Cell Death in the Tumor Microenvironment

“…Likewise, following chemotherapy, dying tumor cells may release HMGB1, a ligand for TLR4 [77], or extracellular DNA, which can be sensed via the pro-inflammatory STING pathway [105]. Like IFNs and TLR ligands, in other settings, STING has been shown to be a potent inducer of IDO [106–108], with consequent suppression of T cell responses. IDO can also be induced by prostaglandins such as PGE2 [109], which can be produced by stressed cells.…”