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Abstract
Background Abnormalities of type I interferon signaling and production can initiate lupus development. Disturbances of nucleic acid-sensing molecules triggered autoreactivity in lupus mouse models. Stimulator of interferon genes (STING) showed various effects in different lupus mouse models, which could be due to the diverse background of the lupus models and Sting-deficient mice. We aim to confirm the function of Sting/Tmem173 in pristane-induced lupus and identify the role of STING/TMEM173 variants in SLE susceptibility.
Methods Pristane-induced lupus model was introduced in the Sting-deficient mice (ENU-induced Goldenticket mutant mice). Autoantibody, histopathology, and immunophenotypes were analyzed after pristane injection for six months. Isolated DNA from 302 SLE patients and 173 healthy donors were tested for STING genotyping. We calculated the Odd Ratios of each STING variant and the inheritance patterns that significantly increased SLE susceptibility. Then, we analyzed the associations between STING genotypes and lupus phenotypes.
Results The absence of STING signaling in the Goldenticket mutant mice reduced the autoantibody production and severity of glomerulonephritis in pristane-induced lupus. The human STING mutation at p.R284S (gain-of-function) significantly increased the SLE risk in autosomal dominant pattern [OR = 64.0860 (95%CI = 22.8605–179.6555), p < 0.0001], while the mutation at p.R232H (loss of function) reduced the SLE risk in autosomal recessive pattern [OR = 0.2515 (95%CI = 0.1648–0.3836), p < 0.0001]. The combination of STING variants in a specific inheritance pattern increased the higher OR than a single variant. The patient who had p.R284S with p.R232H showed milder disease activity than those who had p.R284S alone at the time of diagnosis.
Conclusions The inhibition of STING rescued autoimmune phenotypes in pristane-induced lupus. Gain-of-function STING mutation increased SLE susceptibility and severity of the disease. These data suggested the critical function via STING-mediated signaling in SLE. Targeted at STING may provide a favorable outcome in SLE patients.
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