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 immune-regulatory 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-β. 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.

Anti-Inflammatory Effects of Red Rice Bran Extract Ameliorate Type I Interferon Production via STING Pathway

“…A previous study showed that IFN-I through the STING-mediated pathway promotes the level of IL-10 [ 62 , 63 ]. In contrast, the activation of bone marrow-derived macrophages (BMDM) via cGAS-STING signaling in an allergic encephalomyelitis (EAE) mouse model showed IL-10 production without requiring IFN-I [ 64 ]. Therefore, IL-10 production can also occur through several pathways, including TLR signaling, IFN-I, and nuclear factor kB (NF-kB) [ 65 ].…”

STING Agonist Enhances the Efficacy of PD-L1 Monoclonal Antibody in Breast Cancer Immunotherapy by Activating the IFNβ Signaling Pathway

“…IL-10 is mainly secreted by activated T-cells, which is an important anti-in ammatory cytokine [23]. It has been reported that STING agonist promoted IL-10 expression to relieve mice with experimental autoimmune encephalomyelitis [24]. This research indicated that STING agonist might synergize with Atezolizumab to exert anti-tumor effect by reducing in ammation via increasing IL-10 expression.…”

Intracellular Sensing of DNA in Autoinflammation and Autoimmunity

“…When phagocytosed by myeloid cells, mitochondrial DNA from SLE-derived red blood cells stimulated type I IFN production in a cGAS/STING-dependent manner (75). In contrast, delivery of DNA or cGAMP through microparticles offers protection against disease in animal models of experimental autoimmune encephalomyelitis and type 1 diabetes (76,77). These studies suggest that although endogenous DNA may be a contributing factor to the pathogenesis of certain autoimmune diseases, further studies are needed to better understand its specific role in autoimmunity and the pathways involved and to determine the exact sources of the endogenous DNA at play.…”