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. 2018 Dec 13;26(9):1796–1812. doi: 10.1038/s41418-018-0245-x

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — Erythropoietin (Epo) binds to the Epo receptor (EpoR) to activate erythroid-specific gene transcription (EpoR, globins, glycophorin A (GPA), and miR-144/451) by GATA-1, resulting in hemoglobin (Hb) production. Epo-induced erythropoiesis is concomitant with autophagy flux induction. TNFα binds its receptor TNFR to activate neutral sphingomyelinase (nSMase) catalyzing ceramide (Cer) production. Ceramides inhibit erythroid gene expression and induce GATA-2, PU.1, CD11b, and miR-155, -146a, and -223 expression. TNFα inhibits SphK1 leading to a ceramide/S1P unbalanced reaction. S1P has a positive effect on Hb production and erythroid marker expression. TNFα and ceramides inhibit autophagy. TNFα phosphorylates mTOR (P-mTOR) via the PI3K/AKT pathway, while ceramide activates mTOR through a different mechanism. P-mTOR leads to ULK1 inhibition and the subsequent Atg13 dephosphorylation. TNFα and ceramides inhibit Beclin-1 (BCN1) expression, the formation of the Atg5-Atg12 complex, GFP-LC3 punctae, and autophagosomes, and induce p62/SQSTM1 accumulation. Together, the effects triggered by the TNFα/neutral SMase/ceramide pathway at the molecular level lead to autophagy and erythropoiesis inhibition and myelopoiesis induction