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Mol Med. 2015 Dec 29. doi: 10.2119/molmed.2015.00243. [Epub ahead of print]

HMGB1 mediates anemia of inflammation in murine sepsis survivors.

Author information

1
The Elmezzi Graduate School of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, NY.
2
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY.
3
Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY.
4
Laboratory of Hematopoiesis, The Feinstein Institute for Medical Research, Manhasset, NY.
5
Children's Hospital of Philadelphia, Department of Pediatrics, Division of Hematology, Philadelphia, PA.
6
Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, Manhasset, NY.
7
Departments of Women's and Children's Health, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.
8
Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY.

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 TNF and IL-6 are elevated for five days after the onset of sepsis, and serum HMGB1 levels are increased from day seven until at least day 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±1.7g/dL versus 11.7±1.2g/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.

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