Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling
Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI). In order to investigate the role of signaling by tumor necrosis factor (TNF) in SAVI, we used pharmacological inhibition and genetic inactivation of TNF receptors 1 and 2 in murine SAVI, which is characterized by T cell lymphopenia, inflammatory lung disease and neurodegeneration. Pharmacologic inhibition of TNF signaling improved T cell lymphopenia, but had no effect on interstitial lung disease. Genetic inactivation of TNFR1 and TNFR2, however, rescued the loss of thymocytes, reduced interstitial lung disease and neurodegeneration. Furthermore, genetic inactivation of TNFR1 and TNFR2 blunted transcription of cytokines, chemokines and adhesions proteins, which result from chronic STING activation in SAVI mice. In addition, increased transendothelial migration of neutrophils was ameliorated. Taken together, our results demonstrate a pivotal role of TNFR-signaling in the pathogenesis of SAVI in mice and suggest that available TNFR antagonists could ameliorate SAVI in patients. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/591149v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@177cf0org.highwire.dtl.DTLVardef@b989dorg.highwire.dtl.DTLVardef@150a0c8org.highwire.dtl.DTLVardef@6bd42d_HPS_FORMAT_FIGEXP M_FIG C_FIG