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Activation of the STING Adaptor Attenuates Experimental Autoimmune Encephalitis.

Lookup NU author(s): Dr Henrique De Paula Lemos, Dr Lei Huang, Professor Andrew Mellor

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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.


Publication metadata

Author(s): Lemos H, Huang L, Chandler PR, Mohamed E, Souza GR, Li L, Pacholczyk G, Barber GN, Hayakawa Y, Munn DH, Mellor AL

Publication type: Article

Publication status: Published

Journal: The Journal of Immunology

Year: 2014

Volume: 192

Issue: 12

Pages: 5571-5578

Print publication date: 15/06/2014

Online publication date: 05/05/2014

Acceptance date: 10/04/2014

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: https://doi.org/10.4049/jimmunol.1303258

DOI: 10.4049/jimmunol.1303258

PubMed id: 24799564


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