Apoptosis-derived membrane vesicles drive the cGAS–STING pathway and enhance type I IFN production in systemic lupus erythematosus

Abstract

<jats:sec><jats:title>Objective</jats:title><jats:p>Despite the importance of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) pathogenesis, the mechanisms of IFN-I production have not been fully elucidated. Recognition of nucleic acids by DNA sensors induces IFN-I and interferon-stimulated genes (ISGs), but the involvement of cyclic guanosine monophosphate (GMP)–AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE remains unclear. We studied the role of the cGAS–STING pathway in the IFN-I-producing cascade driven by SLE serum.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We collected sera from patients with SLE (n=64), patients with other autoimmune diseases (n=31) and healthy controls (n=35), and assayed them using a cell-based reporter system that enables highly sensitive detection of IFN-I and ISG-inducing activity. We used Toll-like receptor-specific reporter cells and reporter cells harbouring knockouts of cGAS, STING and IFNAR2 to evaluate signalling pathway-dependent ISG induction.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>IFN-I bioactivity and ISG-inducing activities of serum were higher in patients with SLE than in patients with other autoimmune diseases or healthy controls. ISG-inducing activity of SLE sera was significantly reduced in STING-knockout reporter cells, and STING-dependent ISG-inducing activity correlated with disease activity. Double-stranded DNA levels were elevated in SLE. Apoptosis-derived membrane vesicles (AdMVs) from SLE sera had high ISG-inducing activity, which was diminished in cGAS-knockout or STING-knockout reporter cells.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>AdMVs in SLE serum induce IFN-I production through activation of the cGAS–STING pathway. Thus, blockade of the cGAS–STING axis represents a promising therapeutic target for SLE. Moreover, our cell-based reporter system may be useful for stratifying patients with SLE with high ISG-inducing activity.</jats:p></jats:sec>

Inhibition of Sting rescues lupus disease by the regulation of Lyn-mediated dendritic cell differentiation

“…A gain-of-function mutation in STING has been identified as a responsible gene for a subpopulation of SLE patients, and STING-dependent interferon-inducible genes correlated with disease activity 38,39 . However, there is no functional data of STING in a lupus mouse model that Here, we detected the high expression of Ifi202, Sting, Ifn-β, and interferon-inducible genes from the spleen of these mice.…”

A STING to inflammation and autoimmunity

“…NETs spontaneously produced by SLE patients are more immunogenic for activating STING signaling than the NETs produced by healthy individuals . The SLE patients have higher levels of dsDNA in their serum as compared to the control healthy population …”

“…The apoptosis‐derived membrane vesicles from the sera of SLE patients induce ISGs through cGAS‐STING signaling pathway as the deficiency of each of these components diminishes the production of ISGs and pro‐inflammatory immune response . The role of cGAS‐STING signaling in the exacerbation of other inflammatory (severe eosinophilic asthma, eosinophilic chronic rhinosinusitis, RA, and psoriasis) diseases associated with the frequent release of extracellular traps needs attention .…”

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

“…Systemic lupus erythematosus is a representative model for elucidating the mechanism of type-I interferonopathies. In SLE, the level of self-DNA which is packaged into apoptosis-derived membrane vesicles along with the level of anti-dsDNA antibody is increased in the serum of patients (174). A study revealed increasing levels of ISGs (including cGAS/STING) as well as the cGAMP-detected ratio in peripheral-blood mononuclear cells of SLE patients (175).…”