STING deficiency ameliorates mouse models of lupus and atherosclerosis

Objectives Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome characterized by autoreactive responses to nucleic acids, dysregulation of the type I Interferon (IFN‐I) pathway, and accelerated atherosclerosis. The stimulator of interferon genes (STING), a cytosolic DNA‐sensor, has pathogenic implications in various inflammatory diseases. However, its specific role in SLE pathogenesis, particularly in tissue damage, remains unclear. This study aimed to elucidate the role of STING in murine models of TLR7‐driven lupus and atherosclerosis. Methods A TLR7‐driven lupus model was induced using imiquimod (IMQ) in wild type (WT) and STING knockout (Sting1 ‐/‐ ) mice on a B6 background. Mice were assessed for organ involvement, serum autoantibodies, and innate and adaptive immune responses. Additionally, Sting1 ‐/‐ mice were backcrossed to Apolipoprotein E knockout (Apoe ‐/‐ ) mice, and both Apoe ‐/‐ and Apoe ‐/‐ Sting1 ‐/‐ mice were fed a high‐fat chow (HFC) diet to induce atherosclerosis. Phenotypic assessments were conducted. Results Compared to IMQ‐treated WT mice, Sting1 ‐/‐ mice exhibited reduced disease severity in the lupus‐like phenotype, characterized by decreased splenomegaly, lower renal immune complex deposition and renal damage, diminished expansion of myeloid cells, and reduced activation of T and B lymphocytes. IMQ‐induced DNA release associated with IFN‐β production and subsequent IFN‐induced responses were attenuated in Sting1 ‐/‐ mice. DNase I treatment mitigated IMQ‐induced pro‐inflammatory responses in WT mice but had no effect in Sting1 ‐/‐ mice. Furthermore, STING deficiency conferred protection against vascular damage and reduced atherosclerosis burden, accompanied by decreased IFN‐I production. Human monocyte‐derived macrophages treated with IFN‐I significantly internalized more acetylated LDL when compared to untreated cells, while an association between oxidized nucleic acids and disease activity and vascular damage was found in human SLE. Conclusions These findings highlight a pathogenic role of STING and downstream IFN responses in TLR7‐driven autoimmunity, vascular damage and atherosclerosis, supporting a therapeutic potential for STING inhibition in SLE treatment. Further research is warranted to elucidate the mechanisms underlying STING's involvement in these processes and to explore the feasibility of targeting STING as a therapeutic strategy in SLE and related autoimmune disorders. image