1. Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1 -dependent vasculopathy in mice.
- Author
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Martin GR, Henare K, Salazar C, Scheidl-Yee T, Eggen LJ, Tailor PP, Kim JH, Podstawka J, Fritzler MJ, Kelly MM, Yipp BG, and Jirik FR
- Subjects
- Animals, Biomarkers, Cytokines, Disease Models, Animal, Genetic Association Studies, Humans, Immunohistochemistry, Lymphopenia genetics, Lymphopenia metabolism, Lymphopenia pathology, Membrane Proteins metabolism, Mice, Mice, Transgenic, Molecular Imaging, Organ Specificity, Phenotype, Receptor, Interferon alpha-beta metabolism, Vascular Diseases diagnostic imaging, Vascular Diseases metabolism, Vascular Diseases pathology, Blood Cells metabolism, Gene Expression, Genetic Predisposition to Disease, Membrane Proteins genetics, Mutation, Receptor, Interferon alpha-beta genetics, Vascular Diseases genetics
- Abstract
STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disorder characterized by blood vessel occlusions, acral necrosis, myositis, rashes, and pulmonary inflammation that are the result of activating mutations in the STimulator of Interferon Genes (STING). We generated a transgenic line that recapitulates many of the phenotypic aspects of SAVI by targeting the expression of the human STING-N154S-mutant protein to the murine hematopoietic compartment. hSTING-N154S mice demonstrated failure to gain weight, lymphopenia, progressive paw swelling accompanied by inflammatory infiltrates, severe myositis, and ear and tail necrosis. However, no significant lung inflammation was observed. X-ray microscopy imaging revealed vasculopathy characterized by arteriole occlusions and venous thromboses. Type I interferons and proinflammatory mediators were elevated in hSTING-N154S sera. Importantly, the phenotype was prevented in hSTING-N154S mice lacking the type I interferon receptor gene ( Ifnar1 ). This model, based on a mutant human STING protein, may shed light on the pathophysiological mechanisms operative in SAVI., (© 2019 Martin et al.)
- Published
- 2019
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