HMGB1-Mediated Restriction of EPO Signaling Contributes to Anemia of Inflammation

Dulmovits, Brian M, Tang, Yuefeng, Papoin, Julien, He, Mingzhu, Li, Jianhua, Yang, Huan, Addorisio, Meghan E, Kennedy, Lauren, Khan, Mushran, Brindley, Elena C, Ashley, Ryan J, Ackert-Bicknell, Cheryl, Hale, John, Kurita, Ryo Kurita, Nakamura, Yukio, Diamond, Betty, Barnes, Betsy J, Hermine, Olivier, Gallagher, Patrick G, Steiner, Laurie Ann, Lipton, Jeffrey M, Taylor, Naomi, Mohandas, Narla, Andersson, Ulf, Al-Abed, Yousef, Tracey, Kevin J, Blanc, Lionel (January 2022) HMGB1-Mediated Restriction of EPO Signaling Contributes to Anemia of Inflammation. Blood. ISSN 0006-4971

URL: https://www.ncbi.nlm.nih.gov/pubmed/35040907
DOI: 10.1182/blood.2021012048

Abstract

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 JAK2/STAT5 and mTOR signaling pathways. Genetic ablation of RAGE, 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.

Item Type: Paper
Subjects: diseases & disorders > anemia
diseases & disorders > inflammation
CSHL Authors:
Communities: CSHL labs > Tracey lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 18 January 2022
Date Deposited: 27 Jan 2022 14:18
Last Modified: 27 Jan 2022 14:18
URI: https://repository.cshl.edu/id/eprint/40502

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