Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain

Nociceptive neurons respond to inflammation, initiating protective reflexes and alerting the host. Here we found that TRPV1 nociceptors express and activate the cytosolic DNA-sensing protein Stimulator of Interferon Genes (STING) in response to inflammation. Neuronal activation of STING promotes signaling through TBK1 and triggers a Type I interferon (IFN-I) response. The absence of STING led to heightened pain responses to chemical irritants or heat. In contrast, mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia. Importantly, several IFN-regulated genes (IRGs) were specific to nociceptor ion channels responsible for controlling neuronal activity and pain threshold. Therefore, STING promotes a pain-resolving IFN-I signaling pathway in nociceptors, thereby preventing sensitization and persistent pain Overall design: We performed gene expression profiling analysis using data obtained from RNA-seq between 4 TRPV1cre-GOF mice and 4 littermates controls (GOF).