Colonic immunometabolic host response mechanisms to ionizing radiation in a mouse model of acute radiation syndrome 2260900

Abstract

Abstract Introduction Exposure to high levels of ionizing radiation (IR) causes severe health effects, including acute radiation syndrome (ARS). While some therapeutic options exist to stimulate hematopoiesis, there is an unmet clinical need to develop effective therapeutics for gastrointestinal-ARS (GI-ARS). Methods A global transcriptomics time course (d 0, 1, 2, 3, 5, 7, 10 and 18) was conducted on colon of mice total body-irradiated with a single dose of sublethal (3 and 6 Gy) or lethal (12 Gy) IR to evaluate the gene expression changes associated with mortality or recovery in GI-ARS. Results In the lethal IR dose group, the day preceding mortality marked a transcriptional shift of over 12,000 genes. By clustering differentially expressed genes, twenty distinct temporal patterns were identified. Three notable gene clusters were defined by temporal patterns associated with mortality on d 10 and displayed significant functional enrichment characterized by dysregulated effector immunoinflammatory responses and metabolic disruption. The first cluster identified the upregulation of early (d 3) and late (d 10) inflammation, with enrichment of innate immunity genes. The second cluster was enriched in adaptive immunity genes and was characterized by initial downregulation, followed by an upregulated peak at d 10. The third cluster was characterized by an early downregulation with a secondary decrease on d 10 with an enrichment of sterol metabolism genes. Interestingly, lipid metabolism and sterol metabolism were downregulated at early timepoints followed by later re-stabilization, yet only sterol metabolism was downregulated again on d 10. Conclusion This comprehensive system-wide transcriptional analysis of colonic samples provides new insights into the host response mechanisms underlying IR-induced intestinal damage and subsequent mortality, along with identification of novel immunometabolic mechanisms with strong potential for therapeutic development in GI-ARS. Funding Source N/a Topic Categories Immune Mechanisms of Human Disease (HUM)