Interferon β drives intestinal regeneration after radiation

The cGAS-STING cytosolic DNA sensing pathway is critical for host defense. Here, we report that cGAS-STING–dependent type 1 interferon (IFN) response drives intestinal regeneration and animal recovery from radiation injury. STING deficiency has no effect on radiation-induced DNA damage or crypt apoptosis but abrogates epithelial IFN-β production, local inflammation, innate transcriptional response, and subsequent crypt regeneration. cGAS KO, IFNAR1 KO, or CCR2 KO also abrogates radiation-induced acute crypt inflammation and regeneration. Impaired intestinal regeneration and survival in STING-deficient mice are fully rescued by a single IFN-β treatment given 48 hours after irradiation but not by wild-type (WT) bone marrow. IFN-β treatment remarkably improves the survival of WT mice and Lgr5⁺ stem cell regeneration through elevated compensatory proliferation and more rapid DNA damage removal. Our findings support that inducible IFN-β production in the niche couples ISC injury and regeneration and its potential use to treat acute radiation injury.