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

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 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.

• Authors: Brian M Dulmovits, Yuefeng Tang, Julien Papoin, Mingzhu He, Jianhua Li, Huan Yang, Meghan E Addorisio, Lauren Kennedy, Mushran Khan, Elena Brindley, Ryan J Ashley, Cheryl Ackert-Bicknell, John Hale, Ryo Kurita, Yukio Nakamura, Betty Diamond, Betsy J Barnes, Olivier Hermine, Patrick G Gallagher, Laurie A Steiner, Jeffrey M Lipton, Naomi Taylor, Narla Mohandas, Ulf Andersson, Yousef Al-Abed, Kevin J Tracey, Lionel Blanc
• Journal: Blood (Blood) Vol. 139 Issue 21 Pg. 3181-3193 (05 26 2022) ISSN: 1528-0020 [Electronic] United States
• PMID: 35040907 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022 by The American Society of Hematology.

Chemical References

• Epo protein, mouse
• HMGB1 Protein
• HMGB1 protein, mouse
• Receptors, Erythropoietin
• Erythropoietin

Topics

• Anemia (genetics)
• Animals
• Erythropoiesis (genetics)
• Erythropoietin (metabolism)
• HMGB1 Protein
• Inflammation
• Mice
• Receptors, Erythropoietin (metabolism)
• Sepsis (complications)