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Molecular Medicine

, Volume 21, Issue 1, pp 951–958 | Cite as

HMGB1 Mediates Anemia of Inflammation in Murine Sepsis Survivors

  • Sergio I. Valdés-Ferrer
  • Julien Papoin
  • Meghan E. Dancho
  • Peder S. Olofsson
  • Jianhua Li
  • Jeffrey M. Lipton
  • Patricia Avancena
  • Huan Yang
  • Yong-Rui Zou
  • Sangeeta S. Chavan
  • Bruce T. Volpe
  • Sara Gardenghi
  • Stefano Rivella
  • Betty Diamond
  • Ulf Andersson
  • Bettie M. Steinberg
  • Lionel Blanc
  • Kevin J. Tracey
Research Article

Abstract

Patients surviving sepsis develop anemia, but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating tumor necrosis factor (TNF) and interleukin (IL)-6 are elevated for 5 d after the onset of sepsis, and serum high-mobility group box 1 (HMGB1) levels are increased from d 7 until at least d 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5 ± 9.0% versus 37.4 ± 6.1%, p < 0.01; hemoglobin 14.0 ± 1.7 versus 11.7 ± 1.2 g/dL, p < 0.01). Together, these results indicate that HMGB1 mediates anemia by interfering with erythropoiesis, suggesting a potential therapeutic strategy for anemia in sepsis.

Notes

Acknowledgments

This work was supported by the National Institute of General Medical Sciences (R01-GM57726 and R01-GM62508 to KJ Tracey), the National Institute of Allergy and Infectious Diseases (P01AI102852 to B Diamond and KJ Tracey) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095112 and R01DK090554 to S Rivella). L Blanc is the recipient of an Allied World St. Baldrick’s Scholar Award.

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Copyright information

© The Author(s) 2015

Authors and Affiliations

  • Sergio I. Valdés-Ferrer
    • 1
    • 2
  • Julien Papoin
    • 3
  • Meghan E. Dancho
    • 2
  • Peder S. Olofsson
    • 2
  • Jianhua Li
    • 2
  • Jeffrey M. Lipton
    • 3
  • Patricia Avancena
    • 4
  • Huan Yang
    • 2
  • Yong-Rui Zou
    • 4
  • Sangeeta S. Chavan
    • 2
  • Bruce T. Volpe
    • 2
  • Sara Gardenghi
    • 5
  • Stefano Rivella
    • 5
  • Betty Diamond
    • 6
  • Ulf Andersson
    • 7
  • Bettie M. Steinberg
    • 1
    • 8
  • Lionel Blanc
    • 3
  • Kevin J. Tracey
    • 1
    • 2
  1. 1.Elmezzi Graduate School of Molecular MedicineThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Laboratory of Biomedical ScienceThe Feinstein Institute for Medical ResearchManhassetUSA
  3. 3.Laboratory of Developmental ErythropoiesisThe Feinstein Institute for Medical ResearchManhassetUSA
  4. 4.Laboratory of HematopoiesisThe Feinstein Institute for Medical ResearchManhassetUSA
  5. 5.Department of Pediatrics, Division of HematologyChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  6. 6.Center for Autoimmune and Musculoskeletal DiseaseThe Feinstein Institute for Medical ResearchManhassetUSA
  7. 7.Departments of Women’s and Children’s HealthKarolinska Institute and Karolinska University HospitalStockholmSweden
  8. 8.Center for Oncology and Cell BiologyThe Feinstein Institute for Medical ResearchManhassetUSA

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