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Ann Rheum Dis. 2018 Oct;77(10):1507-1515. doi: 10.1136/annrheumdis-2018-212988. Epub 2018 Jun 26.

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

Kato Y#1,2,3, Park J#2,4, Takamatsu H1,2,3,5, Konaka H1,2,3, Aoki W5,6, Aburaya S5,6, Ueda M5,6, Nishide M1,2,3, Koyama S1,2,3,5, Hayama Y1,2,3, Kinehara Y1,2,3, Hirano T1,2, Shima Y1,2, Narazaki M1,2, Kumanogoh A1,2,3,5.

Author information

1
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
2
Department of Immunopathology, WPI Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.
3
Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan.
4
Graduate School of Medicine, Osaka University, Osaka, Japan.
5
Japan Science and Technology-Core Research for Evolutional Science and Technology (JST-CREST), Osaka University, Osaka, Japan.
6
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
#
Contributed equally

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

autoimmune diseases; cytokines; inflammation; systemic lupus erythematosus

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