Homeostatic erythropoiesis by the transcription factor IRF2 through attenuation of type I interferon signaling.
OBJECTIVE
Erythrocyte production is tightly regulated by cytokines, particularly erythropoietin (EPO), which affects expansion and viability of erythroid lineage cells via induction of several factors, including Bcl2-like 1 (Bcl-XL). Because type I interferon (IFN) is known to inhibit erythropoiesis, we studied mice deficient in the gene for interferon regulatory factor 2 (IRF2), which functions as a negative regulator of type I IFN signaling, in the context of erythropoiesis regulation.


METHODS
We performed hematologic analyses and detected normocytic anemia in Irf2-deficient mice.


RESULTS
Assessment of the maturation of erythroid progenitors in Irf2-deficient bone marrow by flow cytometry revealed a decreased number of late erythroblasts accompanied by an increased number of early erythroid progenitors. Irf2-deficient mice manifested elevated serum EPO levels, decreased Bcl-XL expression levels and enhanced apoptosis of erythroblasts, which may account for the decreased number of late erythroblasts. We further assessed the role of IRF2 in the regulation of type I IFN signaling during erythropoiesis, and found that additional homozygous mutation of IFNAR1, a subunit of type I IFN receptor complex, led to rescue of the defect of erythropoiesis in Irf2-deficient mice.


CONCLUSIONS
Impaired erythropoiesis in Irf2-deficient mice results from excessive type I IFN signaling, which inhibits Bcl-XL expression in erythroid lineage cells. Our present study provides a mechanistic understanding of the potential cross-talk between type I IFN and EPO signaling pathways during erythropoiesis and may offer therapeutic insights into anemia.
Mizutani
Tatsuaki
T
Department of Immunology, Faculty of Medicine and Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Tsuji
Kohichiro
K
Ebihara
Yasuhiro
Y
Taki
Shinsuke
S
Ohba
Yusuke
Y
Taniguchi
Tadatsugu
T
Honda
Kenya
K
D000741:Anemia, Aplastic / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000473:pathology; D015672:Erythroid Precursor Cells / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006403:Hematologic Tests; D050836:Interferon Regulatory Factor-2 / Q000172:deficiency / Q000235:genetics*; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051020:bcl-X Protein / Q000235:genetics
C494812:Bcl2l1 protein, mouse; C508032:Ifnar1 protein, mouse; D050836:Interferon Regulatory Factor-2; D007370:Interferon Type I; C494230:Irf2 protein, mouse; D051020:bcl-X Protein; D053633:Receptor, Interferon alpha-beta