HMGB1-mediated restriction of EPO signaling contributes to anemia of inflammation

• Published in: Blood Vol. 139; no. 21; pp. 3181 - 3193
• Main Authors: Dulmovits, Brian M., Tang, Yuefeng, Papoin, Julien, He, Mingzhu, Li, Jianhua, Yang, Huan, Addorisio, Meghan E., Kennedy, Lauren, Khan, Mushran, Brindley, Elena, Ashley, Ryan J., Ackert-Bicknell, Cheryl, Hale, John, Kurita, Ryo, Nakamura, Yukio, Diamond, Betty, Barnes, Betsy J., Hermine, Olivier, Gallagher, Patrick G., Steiner, Laurie A., Lipton, Jeffrey M., Taylor, Naomi, Mohandas, Narla, Andersson, Ulf, Al-Abed, Yousef, Tracey, Kevin J., Blanc, Lionel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.05.2022; American Society of Hematology
• Subjects: Anemia; Anemia - genetics; Animals; Erythropoiesis; Erythropoiesis - genetics; Erythropoietin; Erythropoietin - metabolism; HMGB1 Protein; Inflammation; Mice; Receptors, Erythropoietin; Receptors, Erythropoietin - metabolism; Red Cells, Iron, and Erythropoiesis; Sepsis; Sepsis - complications
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021012048

Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sepsis, leads to reduced expansion and increased death of EPO-sensitive erythroid precursors in human models of erythropoiesis. HMGB1 significantly attenuates EPO-mediated phosphorylation of the Janus kinase 2/STAT5 and mTOR signaling pathways. Genetic ablation of receptor for advanced glycation end products, the only known HMGB1 receptor expressed by erythroid precursors, does not rescue the deleterious effects of HMGB1 on EPO signaling, either in human or murine precursors. Furthermore, surface plasmon resonance studies highlight the ability of HMGB1 to interfere with the binding between EPO and the EPOR. Administration of a monoclonal anti-HMGB1 antibody after sepsis onset in mice partially restores EPO signaling in vivo. Thus, HMGB1-mediated restriction of EPO signaling contributes to the chronic phase of anemia of inflammation. •HMGB1 alters erythropoiesis by inhibiting the EPO signaling pathway.•HMGB1 affects the EPO signaling pathway independently of RAGE. [Display omitted]