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Effect of the autoimmune suppressor Gadd45a 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 Gadd45 (growth arrest and DNA damage-inducible genes) family is composed of three members, Gadd45a, Gadd45b, and Gadd45g, that play important roles in cell growth control, differentiation, DNA repair, and apoptosis. Gadd45b and Gadd45g are important for inflammatory responses as well as mediating signals of the innate immune system, whereas Gadd45a is a negative regulator of activation-induced T cell proliferation. T cells from Gadd45a null mice are hyper-responsive to activating stimuli due to spontaneously increased p38MAPK activity. Importantly, Gadd45a-deficient mice develop an autoimmune disease, similar to human systemic lupus erythematosus, characterized by severe hematological disorders, kidney disease, and premature death. The goal of this study was to elucidate how pre-existing inflammatory condition in mice can affect radiation biodosimetry. We exposed wild-type and Gadd45a knockout C57BL/6J mice to 7 Gy x-rays and 24 h later we isolated whole blood and performed genome microarray and gene ontology analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE196400 | GEO | 2023/10/20

REPOSITORIES: GEO

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Project description: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.

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Effect of the autoimmune suppressor Gadd45a on radiation biodosimetry

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