Rprm敲除通过CREB-IL-33轴减轻放射性肠损伤

Radiation-induced intestinal injury (RIII) is a common side effect of radiotherapy for solid tumors of the abdomen and pelvis, leading to symptoms such as diarrhea, vomiting, bleeding, enterobrosis, even death. Up to date, there is no effective preventive and therapeutic drug for RIII in clinic. Therefore, it is urgent to perform further study on the underlying mechanisms of RIII to develop effective strategies and drugs to prevent and treat the gastrointestinal toxicities caused by ionizing radiation. Reprimo (RPRM), a tumor suppressor, can be induced by DNA damage after IR exposure and genotoxic agent treatment. Our previous research has demonstrated that RPRM protein plays a critical role in DNA damage repair and radiosensitivity, knocking out mouseRprm gene prolongs the survival time of mice after exposed to radiation, and mitigates radiation-induced brain injury through multiple mechanisms. The expression of RPRM is also abundant in the human small intestine. Our recent study has shown that Rprm knockout alsoalleviates RIII, but the underlying mechanisms remain unknown. The present study first demonstrated that Rprm knockout significantly improved the survival rate of mice after exposed to whole-abdominal irradiation (WBI). Then we identified several differential genes from our previous high-throughput sequencing data and performed validation. We found that compared with wild-type (WT) mice, Rprm knockout (Rprm-/-) mice displayed a significant elevation in IL-33 expression at both transcription and protein levels in the small intestines after WBI. Furthermore, Rprm knockout abolished the reduction of CREB protein level in the small intestines of whole-abdominal irradiated mice and promoted CREB activation, resulting in an elevation in IL-33 expression. More critically, administration of recombinant IL-33 protein or CREB agonist FSK to WT mice prior to WBI dramatically alleviated RIII, while administration of IL-33 antibodies or CREB inhibitor 666-15 to Rprm-/- mice eradicated the relief of RIII caused by Rprm knockout. Taken together, these results indicate that Rprm knockout alleviates RIIII through CREB-IL33 axis. Our results reveal a novel mechanism underlying RIII, and provide a potential preventive and therapeutic target for RIII.