{
  "abstract": "Objectives Type I IFN signature is a well-known hallmark of SLE patients, and this signature is associated with immune activation and inflammation. We suggested that some immune complexes, such as nucleic acid and antibody immune complexes (NA-ICs) trigger a type I IFN signature through innate immune sensors. The dsDNA-immune complex also caused breakdown of mitochondrial homeostasis, further amplifying inflammation and IFN signature in lupus disease.Methods Neutrophils from lupus patients were collected. Our study focuses on dsDNA-immune complex-induced type I IFN signature, NET formation, and pathological change of mitochondria in neutrophils.Bulk RNA sequencing was implemented to investigate the gene profiles in neutrophils derived from SLE patients. We explore why those neutrophils exhibit IFN signatures by examining the factors that induce IFN production and IFN-inducible genes, such as ISG15 expression. The pristane-injection model was used as an animal model in evaluating the IFN signature with neutrophil behavior.Results We showed that the dsDNA-immune complex derived from SLE serum induces ISG15 expression in neutrophils, suggesting that either nucleic acid or protein components integrated into these dsDNA ICs contribute to an IFN signature and NET formation. The Caspase 4-GSDMD axis is involved in the breakdown of mitochondrial homeostasis, targeting the mitochondrial outer membrane. Blocking neutrophils with the GSDMD inhibitor, FcrRIII blocking antibody, and an FDA-approved IFN receptor blockade (Anifrolumab) attenuated the pathological change in mitochondria triggered by dsDNA-immune complex. In an animal study, we examined neutrophil recruitment to the glomerulus in various lupus models, including the pristane-induced lupus-like mouse model, a lupus-prone mouse model, and a model involving pristane injection into lupus-prone mice. We showed that lupus-prone mice (lpr) with pristane injection exhibited Ly6G neutrophil infiltration and IgG deposition in the glomerulus. Lupus mice receiving GSDMD inhibitor treatment exhibited reduced levels of autoantibodies and serum MPO-DNA in GSDMD inhibitor-treated lupus mice. Mice in the treatment group present few levels of NET signal in the glomerulus, with the reduction in IgG deposition in the glomerulus.Abstract PO:01:003 Figure 1Conclusions We demonstrated that dsDNA-immune complex triggers a type I IFN signature and disrupts mitochondrial homeostasis, exacerbating inflammation. Further experiments and mechanisms would be addressed to explain these interesting observations.",
  "authors": [
    {
      "affiliations": [
        "Taipei Veterans General Hospital, Taipei, Taiwan"
      ],
      "name": "Yen Po Tsao"
    },
    {
      "affiliations": [
        "National Yung MIng Chao Tung University, Taipei, Taiwan"
      ],
      "name": "Szu Ting Chen"
    }
  ],
  "title": "PO:01:003 Pathogenic dsDNA-immune complex causes the breakdown of homeostasis in mitochondria, leading to lupus progression",
  "uid": "7d09e86a-dddc-5cc9-8a8a-083b1b1a5cc6"
}