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Effect of the p38 mitogen-activated protein kinase signaling cascade on radiation biodosimetry

ABSTRACT: Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including inflammation, can potentially obscure the predictive power of the method. The mitogen-activated protein kinase (MAPK) p38 is normally regulated by the MAP3K-MAP2K pathway in mammalian cells. Members of the p38 MAPK family respond to pro-inflammatory signals and environmental stresses. However, in T cells there is an alternative pathway for p38MAPK activation. This pathway has been shown to play an important role in antigen-receptor-activated T cells and participate in immune and inflammatory responses. Radiation is known to induce a pro-inflammatory response. To examine the role of p38MAPK in response to radiation, we used two mouse models expressing either a p38αMAPK dominant negative (DN) mutation that would be expected to globally suppress p38MAPK signaling or a double knock-in (DKI) mutant, which would be expected to inhibit specifically T cell receptor activation. We exposed wild-type and p38MAPK mutant mice to 7 Gy x-rays and 24 h later we isolated whole blood and performed genome microarray and gene ontology analysis. Comparison between the two mutants (DN, DKI) suggest that the alternative p38MAPK pathway may have wider functions in the response to radiation exposure beyond its well established role as a downstream effector of activated T-cell receptor. Among the differentially enriched pathways, irradiation leads to a significant overrepresentation of pathways associated with morbidity and mortality as well as organismal cell death. In contrast, these pathways were significantly underrepresented in p38MAPKDN and p38MAPKDKI mutant mice, implying that p38MAPK suppression protects mice from the deleterious effects of radiation. Furthermore, radiation exposure resulted in an enrichment of a small number of phagocytosis-related pathways; however, considerably more phagocytosis-related pathways were overrepresented in the p38MAPK mutant mice, implying that p38MAPK signaling, normally, restricts phagocytosis of apoptotic cells after radiation and may, thus, contribute to persistent inflammation. Finally, despite the significant changes in gene expression, we were still able to identify a panel of genes that could accurately distinguish between irradiated and control mice, irrespective of p38MAPK status.

ORGANISM(S): Mus musculus

PROVIDER: GSE184361 | GEO | 2022/05/06

REPOSITORIES: GEO

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Project description:Introduction Novel biodosimetry assays are needed in the event of radiological/nuclear emergencies for both immediate triage and identifying delayed effects of acute radiation exposure. Genetically engineered mouse models are used to assess how genotypic variation in the general population may affect post-irradiation classification performance. Here, we used a mouse model that lacks the T-cell receptor specific alternative p38 pathway (p38αβY323F, double knock-in [DKI] mice) to determine how attenuated autoimmune and inflammatory responses may affect dose reconstruction. Objectives To determine if deficient alternative p38 activation differentially affects biofluid metabolic signatures post-irradiation compared to wild-type (WT). Methods Untargeted global metabolomics was used to assess biofluid signatures between WT and DKI mice (8 – 10 weeks old) after exposure to total body radiation (0, 2, or 7 Gy). Urine was analyzed in the first week (1, 3, and 7 d) and serum at 1 d. Spectral features of interest were identified using the machine learning algorithm Random Forests and MetaboLyzer. Validated metabolite panels were constructed and classification performance was assessed by determining the area under the receiver operating characteristic curve (AUROC). Results A multidimensional scaling plot showed excellent separation of IR exposed groups in WT with slightly dampened responses in DKI mice. For both urine and serum, excellent sensitivity and specificity (AUROC > 0.90) was observed for 0 Gy vs. 7 Gy groups irrespective of genotype using identical metabolite panels. Similarly, excellent to fair classification (AUROC > 0.75) was observed for ≤ 2 Gy vs. 7 Gy post-irradiation mice for both genotypes, however, model performance declined (AUROC < 0.75) between genotypes post-irradiation. Conclusion Overall, these results suggest less influence of the alternative p38 activation pathway for dose reconstruction compared to other radiosensitive genotypes.

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Effect of the p38 mitogen-activated protein kinase signaling cascade on radiation biodosimetry

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