Role of STING Deficiency in Amelioration of Mouse Models of Lupus and Atherosclerosis.

OBJECTIVE

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 IFN 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 Toll-like receptor 7 (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 ApoeSting1 mice were fed a high-fat chow diet to induce atherosclerosis. Phenotypic assessments were conducted.

RESULTS

Compared with 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 proinflammatory 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 low-density lipoprotein when compared with untreated cells, whereas an association between oxidized nucleic acids and disease activity and vascular damage was found in human SLE.

CONCLUSION

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.