Role of STING/TMEM173 mutation in systemic lupus erythematosus: from animal model to intrinsic human genetics

Objective 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. Conclusion 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research project was supported by the Faculty of Medicine Ramathibodi Hospital (CF_65001), Mahidol University (Basic Research Fund: the fiscal year 2022), the Second Century Fund, Chulalongkorn University (C2F), and International Network for Lupus Research, International Research Network, Thailand (IRN59W0004). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study (MURA2015/731and MURA2021/177)) was approved by the Faculty of Medicine Ramathibodi Hospital ethics committee and conducted according to the guidelines of the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are available upon reasonable request.