Abstract
The stimulator of IFN genes (STING) protein senses cyclic dinucleotides released in response to double-stranded DNA and functions as an adaptor molecule for type I IFN (IFNI) signaling by activating IFNI-stimulated genes (ISG). We found impaired T cell infiltration into the peritoneum in response to TNF-α in global and EC-specific STING–/– mice and discovered that T cell transendothelial migration (TEM) across mouse and human endothelial cells (EC) deficient in STING was strikingly reduced compared with control EC, whereas T cell adhesion was not impaired. STING–/– T cells showed no defect in TEM or adhesion to EC, or immobilized endothelial cell–expressed molecules ICAM1 and VCAM1, compared with WT T cells. Mechanistically, CXCL10, an ISG and a chemoattractant for T cells, was dramatically reduced in TNF-α–stimulated STING–/– EC, and genetic loss or pharmacologic antagonisms of IFNI receptor (IFNAR) pathway reduced T cell TEM. Our data demonstrate a central role for EC-STING during T cell TEM that is dependent on the ISG CXCL10 and on IFNI/IFNAR signaling.
Highlights
Mounting an inflammatory response requires a highly regulated multistep process that involves adhesive interactions of the leukocytes with the vascular endothelium
We report a central role of endothelial cells (EC)-Stimulator of IFN genes (STING) in T cell transendothelial migration (TEM)
We demonstrate that global STING–/– mice have impaired T cell recruitment in response to a TNF-α–induced model of peritonitis compared with WT mice
Summary
Mounting an inflammatory response requires a highly regulated multistep process that involves adhesive interactions of the leukocytes with the vascular endothelium. STING associates with TBK-1, IRF3, activated NF-κB and other factors [3] to form a multimolecular “signalosome” complex that promotes the transcription of IFN-stimulating genes (ISG), such as CXCL10, a chemoattractant for Th1 cells [4,5,6], and ΝF-κΒ–activated genes [7,8,9,10]. In endothelial cells (EC), STING has been primarily studied as an inducer of IFNI responses following viral infections [18]. We report a central role for EC-STING in T cell recruitment and TEM in response to TNF-α in vitro, and in vivo, that is dependent on the ISG CXCL10 and IFN-type I IFN receptor (IFNAR) signaling
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