Hemolysis-driven IFNα production impairs erythropoiesis by negatively regulating EPO signaling in sickle cell disease.

Autor:	Han Y; Laboratory of Membrane Biology, New York Blood Center, New York, NY., Gao C; Laboratory of Membrane Biology, New York Blood Center, New York, NY., Liu Y; Laboratory of Complement Biology, New York Blood Center, New York, NY., Zhang H; Laboratory of Membrane Biology, New York Blood Center, New York, NY., Wang S; Laboratory of Membrane Biology, New York Blood Center, New York, NY., Zhao H; Laboratory of Membrane Biology, New York Blood Center, New York, NY., Bao W; Laboratory of Complement Biology, New York Blood Center, New York, NY., Guo X; Laboratory of Membrane Biology, New York Blood Center, New York, NY., Vinchi F; Laboratory of Iron Research, New York Blood Center, New York, NY., Lobo C; Laboratory of Blood Borne Parasites, New York Blood Center, New York, NY., Shi P; Sickle Cell Clinical Research Program, New York Blood Center, New York, NY., Mendelson A; Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, NY., Luchsinger L; Laboratory of Stem Cell Regenerative Research, New York Blood Center, New York, NY., Zhong H; Laboratory of Immune Regulation, New York Blood Center, New York, NY., Yazdanbakhsh K; Laboratory of Complement Biology, New York Blood Center, New York, NY., An X; Laboratory of Membrane Biology, New York Blood Center, New York, NY.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Mar 14; Vol. 143 (11), pp. 1018-1031.
DOI:	10.1182/blood.2023021658
Abstrakt:	Abstract: Disordered erythropoiesis is a feature of many hematologic diseases, including sickle cell disease (SCD). However, very little is known about erythropoiesis in SCD. Here, we show that although bone marrow (BM) erythroid progenitors and erythroblasts in Hbbth3/+ thalassemia mice were increased more than twofold, they were expanded by only ∼40% in Townes sickle mice (SS). We further show that the colony-forming ability of SS erythroid progenitors was decreased and erythropoietin (EPO)/EPO receptor (EPOR) signaling was impaired in SS erythroid cells. Furthermore, SS mice exhibited reduced responses to EPO. Injection of mice with red cell lysates or hemin, mimicking hemolysis in SCD, led to suppression of erythropoiesis and reduced EPO/EPOR signaling, indicating hemolysis, a hallmark of SCD, and could contribute to the impaired erythropoiesis in SCD. In vitro hemin treatment did not affect Stat5 phosphorylation, suggesting that hemin-induced erythropoiesis suppression in vivo is via an indirect mechanism. Treatment with interferon α (IFNα), which is upregulated by hemolysis and elevated in SCD, led to suppression of mouse BM erythropoiesis in vivo and human erythropoiesis in vitro, along with inhibition of Stat5 phosphorylation. Notably, in sickle erythroid cells, IFN-1 signaling was activated and the expression of cytokine inducible SH2-containing protein (CISH), a negative regulator of EPO/EPOR signaling, was increased. CISH deletion in human erythroblasts partially rescued IFNα-mediated impairment of cell growth and EPOR signaling. Knocking out Ifnar1 in SS mice rescued the defective BM erythropoiesis and improved EPO/EPOR signaling. Our findings identify an unexpected role of hemolysis on the impaired erythropoiesis in SCD through inhibition of EPO/EPOR signaling via a heme-IFNα-CISH axis. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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