Compound Deficiency of Nrf2 and Selenoproteins in Hematopoietic Cells Leads to Severe Defects in Erythroid and Lymphoid Lineage Development.

Abstract 1993 Poster Board I-1015 Precise regulation of reactive oxygen species (ROS) level is essential for normal cellular homeostasis. Defect of ROS scavenging system results in excess accumulation of ROS in cells, leading to the cellular aging and senescence. Nrf2 (NF-E2-related factor 2) is a basic leucine zipper-type transcription factor, which regulates expression of a set of genes related to the ROS scavenging and detoxification. While accumulating lines of evidence support the significance of Nrf2 for the cellular protection in many types of cells, Nrf2-deficient mice live out their natural life span under the homeostatic condition, and show no significant hematological abnormality except for anemia with aging. We previously found that the Nrf2 activity rose in the macrophages and liver cells derived from conditional knockout (CKO) mice of the selenocystein tRNA ( Trsp ) gene. The Trsp gene is essential for production of selenoproteins, including glutathione peroxidase and thioredoxin reductase. Thus, there are two prevalent ROS scavenging systems based on different molecular mechanisms; Nrf2 and selenoproteins seemingly act compensatory and cooperatively for maintenance of hematopoietic homeostasis. To explore the roles Nrf2 and selenoproteins play in hematopoietic cells, we conducted conditional knockout of the Trsp gene by crossing Trsp -floxed mice with the interferon-inducible Mx1-Cre transgenic mice in combination with Nrf2 gene knockout (KO) in germline. The Trsp -CKO mice in the background of Nrf2 wild type ( Trsp single KO mice) showed thymic atrophy with massive reduction of CD4/CD8 double-positive cells in thymus. This T-lymphocytic phenotype was not changed in the Trsp -CKO mice under the circumstance of Nrf2-null condition ( Trsp:Nrf2 double KO mice), suggesting that selenoproteins were prerequisite for the T-cell development. The Trsp single KO mice suffered from mild anemia with increased number of erythroid progenitors in bone marrow and spleen, and importantly this erythroid phenotype was dramatically exacerbated in the Trsp:Nrf2 double KO mice. A large number of poikilocytes and teardrop-shaped cells were observed in the blood smear of the Trsp:Nrf2 double KO mice, whereas these deformed red blood cells were vaguely found in the Trsp single KO mice. Intracellular ROS level was significantly elevated in erythroid progenitors recovered from the Trsp:Nrf2 double KO mice, although that of the Trsp single KO mice were maintained within normal level, indicating that Nrf2 compensates for the defect of ROS scavenging function caused by the loss of selenoproteins in erythroid cells. These results thus demonstrate for the first time that the ROS scavenging conducted by Nrf2 and selenoproteins is essential for the homeostatic maintenance in erythroid and lymphoid cells in a lineage-specific manner. Disclosures: No relevant conflicts of interest to declare.