Expression of a constitutively active humanSTINGmutant in hematopoietic cells produces anIfnar1-dependent vasculopathy in mice

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-N154Smice 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 inhSTING-N154Ssera. Importantly, the phenotype was prevented inhSTING-N154Smice 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.

Molecular and spatial mechanisms governing STING signalling

“…Collectively these findings suggest that the phenotype of murine SAVI is largely IFN-independent. In contrast, the SAVI disease pathology observed in mice expressing transgenic human STING N154S appeared to be highly dependent on Ifnar expression [158]. Of note, human STING N154S mice failed to develop any significant lung pathology [158], which is a hallmark clinical feature of SAVI patients and mice.…”

“…In contrast, the SAVI disease pathology observed in mice expressing transgenic human STING N154S appeared to be highly dependent on Ifnar expression [158]. Of note, human STING N154S mice failed to develop any significant lung pathology [158], which is a hallmark clinical feature of SAVI patients and mice. Interestingly, T cells from N153S SAVI mice appear to undergo significant cell death, linked to ER stress and the unfolded protein response (UPR) [159].…”

“…This article is protected by copyright. All rights reserved lung pathology [158], which is a hallmark clinical feature of SAVI patients and mice. Interestingly, T cells from N153S SAVI mice appear to undergo significant cell death, linked to ER stress and the unfolded protein response (UPR) [159].…”

The role of cGAS/STING in intestinal immunity

“…Hyperactivation of STING as a consequence of these gain-of-function mutations and subsequent type I IFN production then results in sterile inflammation, mainly affecting the skin and the lungs [7,69]. In opposition to AGS, despite severe systemic inflammation, neither gastrointestinal lesions have been described in the original publication, nor have gastrointestinal affections been evaluated and described in any mouse models investigating SAVI [7,[70][71][72][73].…”

Immune Regulation of the cGAS-STING Signaling Pathway in the Tumor Microenvironment and Its Clinical Application

“…Recent studies found that the abnormal activation of STING leads to immune dysfunction and induces autoimmune diseases such as Aicardi-Goutieres syndrome, systemic lupus erythematosus, and STING-associated vasculopathy with onset in infancy (SAVI), drawing attention to the need for the development of STING inhibitors. [129][130][131] Two nitrofuran derivatives, C-178 and C-176, covalently act on the predicted transmembrane cysteine residue Cys91, thus blocking activated STING by palmitoylation. The species-specificity of C-178 and C-176 indicated that the compounds were targeted to mouse STING (mmSTING) and not to human STING (hsSTING).…”