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Life Sci Alliance. 2019 Jun 20;2(3). pii: e201800215. doi: 10.26508/lsa.201800215. Print 2019 Jun.

Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1-dependent vasculopathy in mice.

Author information

1
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada marting@ucalgary.ca.
2
The McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, Calgary, Canada.
3
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada.
4
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
5
Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada.
6
Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada.
7
Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada.
8
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada jirik@ucalgary.ca.

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.

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