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

Yubin Li, Christina Bax, Jay Patel, Thomas Vazquez, Adarsh Ravishankar, Muhammad M Bashir, Madison Grinnell, DeAnna Diaz, Victoria P Werth, Yubin Li, Christina Bax, Jay Patel, Thomas Vazquez, Adarsh Ravishankar, Muhammad M Bashir, Madison Grinnell, DeAnna Diaz, Victoria P Werth

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: dermatomyositis; dsDNA; extracellular vesicles; stimulator of interferon genes; type I interferon.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

© The author(s).

Figures

Figure 1
Figure 1
DM plasma-derived small extracellular vesicles are different compared to HC plasma-derived small extracellular vesicles. (A) Concentration and size distribution of small extracellular vesicles (sEVs) derived from HC plasma vs. DM plasma. (B) Total number of sEVs derived from HC plasma (4.545x1011 ± 4.019x1011 particles/mL, n = 7) and DM plasma (1.309x1012 ± 6.377x1011 particles/mL, n = 11). (C) Average size of sEVs derived from healthy plasma (83.69 ± 1.057 nm, n = 7) and DM plasma (75.33 ± 3.786 nm, n = 11). (D) Number of EVs with different surface markers CD81, CD9, and CD63 from 35 µL of HC plasma (n = 3) and DM plasma (n = 3). (E) Corresponding density of EVs with different surface makers CD81, CD9, and CD63 from HC plasma and DM plasma. (F) Representative immunoblot showing expression level of surface makers CD81, CD9, and CD63 in 0.5 µL of HC plasma (n = 3) vs DM plasma (n = 3). (G) Expression level relative intensity of CD81, CD9, and CD63 in 0.5 µL of HC plasma (n = 6) vs DM plasma (n = 6). Data in (B,C,D,G) represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 between groups as indicated. Comparison between two groups was analyzed by the Student t test.
Figure 2
Figure 2
DM plasma-derived extracellular vesicles triggered more pro-inflammatory cytokine release in PBMCs than HC plasma-derived extracellular vesicles. 100 µL of PBS-resuspended EVs derived from 1mL plasma of 5 healthy donors and 14 DM patients were used to stimulate PBMCs (1.5x106/mL, 2 mL/well) for 15 h. The supernatants were collected for interferon β (IFNβ), tumor necrosis factor α (TNFα), and interleukin 6 (IL-6) detection. (A) DM plasma-derived EVs triggered more IFNβ release (25.39 ± 5.700 pg/mL, n = 14) than HC plasma-derived EVs (4.285 ± 2.727 pg/mL, n = 5). (B) DM plasma-derived EVs triggered more TNFα release (1193 ± 561.8 pg/mL, n = 14) than HC plasma-derived EVs (329.0 ± 244.9 pg/mL, n = 5). (C) DM plasma-derived EVs triggered more IL6 release (600.2 ± 240.0 pg/mL, n = 14) than HC plasma-derived EVs (264.6 ± 31.30 pg/mL, n = 5). (D) DM plasma-derived EVs induced more STING phosphorylation than healthy plasma-derived EVs in PBMCs. (E) Relative intensity of phosphorylated STING in DM plasma- or HC plasma-derived EVs stimulated PBMCs (n = 3). Data in (A,B,C,E) represent mean ± SD. *P < 0.05, ***P < 0.001 between groups as indicated. Comparison between two groups was analyzed by the Student t test.
Figure 3
Figure 3
DM plasma derived extracellular vesicles induced STING phosphorylation during their triggered pro-inflammatory response in PBMCs. (A) Representative immunofluorescent staining images showing that EVs derived from DM plasma induced phosphorylation of STING in PBMCs. (Scale bar 100 µm) (B) Bar graph depicting the relative intensity of phosphorylated STING immunofluorescent staining in PBMCs with/without DM plasma-derived EVs stimulation (n = 5). (C) DM plasma-derived small EVs (sEVs) triggered more IFNβ release(30.24 ± 1.302 pg/mL, n = 4) than large EVs (lEVs) (7.22 ± 0.9899 pg/mL, n = 4) in PBMCs; DM plasma-derived sEVs (1407 ± 247.0 pg/mL, n = 4) triggered more TNFα release than lEVs (269.9 ± 62.53 pg/mL, n = 4) in PBMCs; DM plasma-derived sEVs (886.2 ± 120.4 pg/mL, n = 4) triggered more IL6 release than lEVs (468.7 ± 75.15 pg/mL, n = 4) in PBMCs. (D) Graph of DM Activity of Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) vs. DM sEVs concentration (n = 11) and lEVs concentration (n = 7). R2 = coefficient of correlation. Data in B represent median, data in C represent mean ± SD. **P < 0.01, ***P < 0.001 between groups as indicated. Comparison between two groups was analyzed by the Student t test.
Figure 4
Figure 4
Inhibition of STING impaired immunostimulatory effects of DM plasma derived small extracellular vesicles in PBMCs. (A) sEVs-stimulated PBMCs secreted less IFNβ release when STING antagonist H-151 (1μM) was present ((21.58 ± 5.45 vs. 28.34 ± 4.25) pg/mL; n = 6). (B) sEVs-stimulated PBMCs secreted less TNFα release when STING antagonist H-151 was present (434.8 ± 231.5 vs. 919.1 ± 325.7) pg/mL; n = 6). (C) sEVs-stimulated PBMCs secreted less IL6 release when STING antagonist H-151 was present ((611.5 ± 132.8 vs. 844.2 ± 180.3) pg/mL; n = 6). (D) STING antagonist H-151 suppressed DM plasma-derived sEV-induced STING phosphorylation and its downstream signaling pathway TBK1, IRF3, and NFκB phosphorylation in PBMCs. (E) Relative intensity of phosphorylated STING, phosphorylated TBK1, phosphorylated IRF3, and phosphorylated NFκB in PBMCs stimulated with/without DM derived sEVs in the presence/absence of STING antagonist H-151 (n = 3). Data in (A,B,C,E) represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 between groups as indicated. Comparison among three or more groups was performed using ANOVA, followed by Student-Newman-Keuls test. Comparison between two groups was analyzed by the Student t test.
Figure 5
Figure 5
Silencing of STING suppressed immunostimulatory effects of DM plasma derived small extracellular vesicles in PBMCs. (A) Representative immunoblot images showed that total STING level was decreased in siSTING transfected PBMCs, and DM plasma-derived sEVs induced more STING phosphorylation in siCTRL transfected PBMCs than siSTING transfected PBMCs. (B) DM plasma-derived sEVs induced more STING phosphorylation in siCTRL transfected PBMCs than siSTING transfected PBMCs (n = 3). (C) Total STING level was decreased in siSTING transfected PBMCs (n = 3). (D) DM plasma-derived sEVs induced more IFNβ release in siCTRL transfected PBMCs (29.32 ± 4.299 pg/mL; n = 5) than siSTING transfected PBMCs (17.18 ± 6.531 pg/mL; n = 5). Data in (B,C,D) represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 between groups as indicated. Comparison among three or more groups was performed using ANOVA, followed by Student-Newman-Keuls test.
Figure 6
Figure 6
Inhibition of TBK1 decreased DM plasma derived small extracellular vesicles' immunostimulatory effects in PBMCs. (A) Representative immunofluorescent staining images showing that sEVs derived from DM plasma induced phosphorylation of TBK1 in PBMCs. (Scale bar 100 µm) (B) Bar graphic depicting the relative intensity of phosphorylated TBK1 immunofluorescent staining in PBMCs with/without DM plasma-derived sEVs stimulation (n = 5). (C) TBK1 inhibitors suppressed DM plasma-derived sEVs induced TBK1 and IRF3 phosphorylation in PBMCs. (D) DM plasma-derived sEVs induced IFNβ release in PBMCs (11.40 ± 4.669 pg/mL, n = 5) when compared with untreated PBMCs (2.000 ± 0.7674 pg/mL, n = 5). 2.5 µM of Amlexanox (TBK1 inhibitor) pretreatment impaired sEVs-triggered IFNβ release in PBMCs (3.933 ± 2.002 pg/mL, n = 5); 2.5 µM of MRT67307 (TBK1 inhibitor) pretreatment impaired DM sEVs-triggered IFNβ release in PBMCs (4.067 ± 1.511 pg/mL, n = 5). Data in B represent median. Data in D represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 between groups as indicated. Comparison between two groups was analyzed by the Student t test. Comparison among three or more groups was performed using ANOVA, followed by Student-Newman-Keuls test.
Figure 7
Figure 7
Digestion of DM plasma-derived small extracellular vesicles-captured DNA impaired their triggered pro-inflammatory response in PBMCs. (A) Pre-treatment with Triton X-100 and DNase (DNase I or dsDNase) attenuated sEVs ability to trigger IFNβ release in PBMCs (n = 3-6). (B) Pre-treatment with Triton X-100 and DNase (DNase I or dsDNase) attenuated sEVs ability to trigger TNFα release in PBMCs (n = 3-6). (C) Pre-treatment with Triton X-100 and DNase (DNase I or dsDNase) attenuated sEVs ability to trigger IL6 release in PBMCs (n = 3-6). (D) Genomic/mitochondrial DNA captured by EVs in the presence/absence of 0.075% Triton X-100 with/without DNase I was assessed by PCR using relative specified primers. (E) Genomic/mitochondrial DNA captured by EVs in the presence/absence of 0.075% Triton X-100 with/without dsDNase was assessed by PCR using relative specified primers. Data in (A,B,C) represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 between groups as indicated. Comparison among three or more groups was performed using ANOVA, followed by Student-Newman-Keuls test.
Figure 8
Figure 8
Digestion of DM plasma-derived small extracellular vesicles-captured DNA impaired their triggered STING signaling pathway activation in PBMCs. (A) The effects of DM plasma derived sEVs pretreated in the presence/absence of 0.075% Triton X-100 with/without DNase I on STING phosphorylation and its downstream signaling pathway TBK1, and IRF3 phosphorylation in PBMCs. (B) The effects of DM plasma derived sEVs pretreated in the presence/absence of 0.075% Triton X-100 with/without dsDNase on STING phosphorylation and its downstream signaling pathway TBK1, and IRF3 phosphorylation in PBMCs. Relative intensity of phosphorylated STING (C), phosphorylated TBK1(D), and phosphorylated IRF3 (E) in PBMCs stimulated by DM plasma derived sEVs pretreated in the presence/absence of 0.075% Triton X-100 with/without DNase I (n = 3). Relative intensity of phosphorylated STING (F), phosphorylated TBK1(G), and phosphorylated IRF3 (H) in PBMCs stimulated by DM plasma derived sEVs pretreated in the presence/absence of 0.075% Triton X-100 with/without dsDNase (n = 3). Data were represent mean ± SD. *P < 0.05,**P < 0.01 between groups as indicated. Comparison among three or more groups was performed using ANOVA, followed by Student-Newman-Keuls test.

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