Browse by author
Lookup NU author(s): Dr Henrique De Paula LemosORCiD, Dr Lei HuangORCiD, Emeritus Professor Andrew MellorORCiD
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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.
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
Altmetrics provided by Altmetric
