GSE244062 Tissue-specific inflammation induced by constitutively active STING is mediated by enhanced TNF signaling

Contributors : Rayk Behrendt ; Hella Luksch ; Angela R ösen-WolffSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusConstitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI) in humans and in mice. Murine SAVI is characterized by T cell lymphopenia, severe inflammatory interstitial lung disease, neuroinflammation and neurodegeneration with only limited contribution of type I interferon signaling. Here, we show that pharmacologic inhibition of TNF signaling in SAVI mice improved T cell lymphopenia, but had no effect on interstitial lung disease. However, complete blocking of TNF receptor signaling by knocking out TNFR1 and TNFR2 in SAVI mice rescued both, loss of thymocytes as well as interstitial lung disease. Furthermore, chronic STING signaling in lung endothelial cells of diseased mice enhanced transcription of cytokines, chemokines and adhesions proteins resulting in increased transendothelial migration of neutrophils across the endothelial barrier that could be reverted by genetic inactivation of TNFR1 and 2. Thus, our results demonstrate a pivotal role of TNFR-signaling in the development of SAVI-associated lung disease and suggest this pathway as promising target to ameliorate human SAVI
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research