Exploring endothelial dysfunction in SLE: cGAS-STING-IRF3 pathway activation by dsDNA.

Area of Science:

• Immunology
• Vascular Biology
• Molecular Medicine

Background:

• Systemic lupus erythematosus (SLE) is linked to anti-double stranded DNA (anti-dsDNA) antibodies and endothelial dysfunction.
• The precise mechanisms connecting extracellular DNA to vascular injury in SLE are not fully understood.

Purpose of the Study:

• To investigate the direct impact of extracellular double-stranded DNA (dsDNA) on endothelial cells.
• To elucidate the molecular pathways involved in dsDNA-induced endothelial injury.
• To correlate these findings with endothelial dysfunction markers in SLE patients.

Main Methods:

• Collected clinical samples from SLE patients and healthy controls.
• Utilized human umbilical vein endothelial cells (HUVECs) for in vitro studies.
• Employed cell viability assays, ELISA, RT-qPCR, Western blot, and immunofluorescence to assess endothelial injury and signaling pathways.

Main Results:

• SLE patients, especially those with anti-dsDNA antibodies, exhibited elevated serum levels of von Willebrand factor (vWF), soluble thrombomodulin (sTM), and E-selectin.
• In vitro, dsDNA exposure reduced HUVEC viability and upregulated vWF, sTM, and E-selectin secretion.
• dsDNA activated the cGAS-STING-IRF3 signaling pathway in endothelial cells, confirmed by increased gene and protein expression and enhanced cGAS localization.

Conclusions:

• Cell-free dsDNA directly induces endothelial dysfunction via the cGAS-STING-IRF3 pathway.
• This mechanism contributes to vascular injury observed in SLE.
• The cGAS-STING-IRF3 axis presents a potential therapeutic target for SLE and related conditions.