RT Journal Article
SR Electronic
T1 Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1-dependent vasculopathy in mice
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800215
DO 10.26508/lsa.201800215
VO 2
IS 3
A1 Martin, Gary R
A1 Henare, Kimiora
A1 Salazar, Carolina
A1 Scheidl-Yee, Teresa
A1 Eggen, Laura J
A1 Tailor, Pankaj P
A1 Kim, Jung Hwan
A1 Podstawka, John
A1 Fritzler, Marvin J
A1 Kelly, Margaret M
A1 Yipp, Bryan G
A1 Jirik, Frank R
YR 2019
UL http://www.life-science-alliance.org/content/2/3/e201800215.abstract
AB 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.