Title: IL-17F induces inflammation, dysfunction and cell death in mouse islets
Authors: Catterall, T
Fynch, S
Kay, TWH
Thomas, HE
Sutherland, APR
Issue Year: 2020
Publisher NATURE PUBLISHING GROUP
Series SCIENTIFIC REPORTS:
Abstract Erythropoiesis is intimately coupled to cell division, and deletion of the cell cycle regu-lator retinoblastoma protein (pRb) causes anemia in mice. Erythroid-specific deletion of pRb has been found to result in inefficient erythropoiesis because of deregulated coordination of cell cycle exit and mitochondrial biogenesis. However, the pathophysi-ology remains to be fully described, and further characterization of the link between cell cycle regulation and mitochondrial function is needed. To this end we further assessed conditional erythroid-specific deletion of pRb. This resulted in macrocytic ane-mia, despite elevated levels of erythropoietin (Epo), and an accumulation of erythroid progenitors in the bone marrow, a phenotype strongly resembling refractory anemia associated with myelodysplastic syndromes (MDS). Using high-fractionation fluores-cence-activated cell sorting analysis for improved phenotypic characterization, we illus-trate that erythroid differentiation was disrupted at the orthochromatic stage. Transcriptional profiling of sequential purified populations revealed failure to upregu-late genes critical for mitochondrial function such as Pgc1b, Alas2, and Abcb7 specifi-cally at the block, together with disturbed heme production and iron transport. Notably, deregulated ABCB7 causes ring sideroblastic anemia in MDS patients, and the mitochondrial co-activator PGC1b is heterozygously lost in del5q MDS. Importantly, the anemia could be rescued through enhanced PPAR signaling in vivo via either over-expression of Pgc1b or bezafibrate administration. In conclusion, lack of pRb results in MDS-like anemia with disrupted differentiation and impaired mitochondrial function at the orthochromatic erythroblast stage. Our findings reveal for the first time a role for pRb in heme and iron regulation, and indicate that pRb-induced anemia can be rescued in vivo through therapeutic enhancement of PPAR signaling. (c) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
URI: https://publications.svi.edu.au/publications/7078
Other Identifiers 10.1038/s41598-020-69805-2
Publication type Article