Theranostics 2021; 11(15):7144-7158. doi:10.7150/thno.59152 This issue Cite

Research Paper

Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis

Yubin Li1,2, Christina Bax1,2, Jay Patel1,2, Thomas Vazquez1,2, Adarsh Ravishankar1,2, Muhammad M. Bashir1,2, Madison Grinnell1,2, DeAnna Diaz1,2, Victoria P. Werth1,2✉

1. Corporal Michael J. Crescenz Veterans Affairs Medical Center Philadelphia, PA.
2. Department of Dermatology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Citation:
Li Y, Bax C, Patel J, Vazquez T, Ravishankar A, Bashir MM, Grinnell M, Diaz D, Werth VP. Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis. Theranostics 2021; 11(15):7144-7158. doi:10.7150/thno.59152. https://www.thno.org/v11p7144.htm
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Abstract

Graphic abstract

Objectives: Extracellular vesicles (EVs) are lipid bilayer membrane vesicles that are present in various bodily fluids and have been implicated in autoimmune disease pathogenesis. Type I interferons (IFN), specifically IFN-β, are uniquely elevated in dermatomyositis (DM). The stimulator of interferon genes (STING) works as a critical nucleic acid sensor and adaptor in type I IFN signaling with possible implications in autoimmune diseases such as DM. In the current study, we investigated whether circulating EVs contribute to proinflammatory effects in DM, whether these proinflammatory responses are mediated by the STING signaling pathway, and if so, by what mechanism STING is activated.

Methods: We collected and characterized EVs from plasma of healthy controls (HC) and DM patients; analyzed their abilities to trigger proinflammatory cytokines release by ELISA, and explored STING signaling pathway activation using immunoblot and immunofluorescent staining. STING signaling pathway inhibitors and RNAi were used to further investigate whether STING was involved in EVs-triggered proinflammatory response. DNase/lipid destabilizing agent was utilized to digest EVs and their captured DNA contents to evaluate how EVs triggered STING-mediated proinflammatory response in DM.

Results: EVs isolated from DM plasma triggered proinflammatory cytokines including type I IFN release with STING signaling pathway activation. The activated STING pathway was preferentially mediated by dsDNA captured by EVs. Suppression of STING or its downstream signaling proteins attenuated the EVs-mediated proinflammatory response.

Conclusions: Plasma-derived, DNA containing-EVs induced STING-mediated proinflammatory effects in DM. Targeting the STING pathway may be a potential therapeutic approach for DM.

Keywords: extracellular vesicles, dsDNA, type I interferon, stimulator of interferon genes, dermatomyositis


Citation styles

APA
Li, Y., Bax, C., Patel, J., Vazquez, T., Ravishankar, A., Bashir, M.M., Grinnell, M., Diaz, D., Werth, V.P. (2021). Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis. Theranostics, 11(15), 7144-7158. https://doi.org/10.7150/thno.59152.

ACS
Li, Y.; Bax, C.; Patel, J.; Vazquez, T.; Ravishankar, A.; Bashir, M.M.; Grinnell, M.; Diaz, D.; Werth, V.P. Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis. Theranostics 2021, 11 (15), 7144-7158. DOI: 10.7150/thno.59152.

NLM
Li Y, Bax C, Patel J, Vazquez T, Ravishankar A, Bashir MM, Grinnell M, Diaz D, Werth VP. Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis. Theranostics 2021; 11(15):7144-7158. doi:10.7150/thno.59152. https://www.thno.org/v11p7144.htm

CSE
Li Y, Bax C, Patel J, Vazquez T, Ravishankar A, Bashir MM, Grinnell M, Diaz D, Werth VP. 2021. Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis. Theranostics. 11(15):7144-7158.

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