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Apoptosis-derived membrane vesicles drive the cGAS–STING pathway and enhance type I IFN production in systemic lupus erythematosus
  1. Yasuhiro Kato1,2,3,
  2. JeongHoon Park2,4,
  3. Hyota Takamatsu1,2,3,5,
  4. Hachirou Konaka1,2,3,
  5. Wataru Aoki5,6,
  6. Syunsuke Aburaya5,6,
  7. Mitsuyoshi Ueda5,6,
  8. Masayuki Nishide1,2,3,
  9. Shohei Koyama1,2,3,5,
  10. Yoshitomo Hayama1,2,3,
  11. Yuhei Kinehara1,2,3,
  12. Toru Hirano1,2,
  13. Yoshihito Shima1,2,
  14. Masashi Narazaki1,2,
  15. Atsushi Kumanogoh1,2,3,5
  1. 1 Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
  2. 2 Department of Immunopathology, WPI Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan
  3. 3 Japan Agency for Medical Research and Development – Core Research for Evolutional Science and Technology (AMED–CREST), Osaka University, Osaka, Japan
  4. 4 Graduate School of Medicine, Osaka University, Osaka, Japan
  5. 5 Japan Science and Technology–Core Research for Evolutional Science and Technology (JST–CREST), Osaka University, Osaka, Japan
  6. 6 Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
  1. Correspondence to Dr Hyota Takamatsu, Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; thyota{at}imed3.med.osaka-u.ac.jp

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.

  • systemic lupus erythematosus
  • inflammation
  • cytokines
  • autoimmune diseases

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Footnotes

  • YK and JHP contributed equally.

  • Handling editor Josef S Smolen

  • Contributors HT and YKa designed the project. YKa and JP performed most experiments. YKa analysed the data. HT, YKa and JP wrote the manuscript. SA and WA performed the MS analysis. HK assisted with the experiments. SK, YH and YKi participated in the discussions. MNi, TH, YS and MNa collected clinical samples and provided critical suggestions. MU provided critical collaborative suggestions regarding the MS analysis. AK oversaw the study.

  • Funding This study was supported in part by a research grant from JSPS KAKENHI (15K09550, to HT); a Core Research for Evolutionary Science and Technology (CREST) grant from the Japan Science and Technology Agency (JST) (JPMJCR16G2, to HT and MU); the Naito Foundation (to HT); the Center of Innovation Program (COI-STREAM) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) (to AK); Japan Agency for Medical Research and Development (AMED)-CREST grant (15652237, to AK); and MEXT Grant-in-Aid (14525051, to AK).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Enrolment of all participants was approved by the institutional review boards of Osaka University. Informed consent was obtained from all subjects in accordance with the Declaration of Helsinki and with approval of the ethical review board of Osaka University (no 12456-3 and 11122-4).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are available from the corresponding author upon request.

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