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Department of Medicine, University of Alabama, Birmingham, AL 35294
Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical to resolution of inflammation. Impaired efferocytosis is associated with an unfavorable outcome from inflammatory diseases, including acute lung injury and pulmonary manifestations of cystic fibrosis. High mobility group protein-1 (HMGB1), a nuclear nonhistone DNA-binding protein, has recently been found to be secreted by immune cells upon stimulation with LPS and cytokines. Plasma and tissue levels of HMGB1 are elevated for prolonged periods in chronic and acute inflammatory conditions, including sepsis, rheumatoid arthritis, acute lung injury, burns, and hemorrhage. In this study, we found that HMGB1 inhibits phagocytosis of apoptotic neutrophils by macrophages in vivo and in vitro. Phosphatidylserine (PS) is directly involved in the inhibition of phagocytosis by HMGB1, as blockade of HMGB1 by PS eliminates the effects of HMGB1 on efferocytosis. Confocal and fluorescence resonance energy transfer demonstrate that HMGB1 interacts with PS on the neutrophil surface. However, HMGB1 does not inhibit PS-independent phagocytosis of viable neutrophils. Bronchoalveolar lavage fluid from Scnn+ mice, a murine model of cystic fibrosis lung disease which contains elevated concentrations of HMGB1, inhibits neutrophil efferocytosis. Anti-HMGB1 Abs reverse the inhibitory effect of Scnn+ bronchoalveolar lavage on efferocytosis, showing that this effect is due to HMGB1. These findings demonstrate that HMGB1 can modulate phagocytosis of apoptotic neutrophils and suggest an alternative mechanism by which HMGB1 is involved in enhancing inflammatory responses.
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1 This work was supported by Grants P01 HL068743 and P50 GM049222 (to E.A.) from the National Institutes of Health.
2 G.L. and J.W. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Edward Abraham, Professor and Chair, Department of Medicine, University of Alabama, School of Medicine, 420 Boshell Building, 1808 7th Avenue South, Birmingham, AL 35294. E-mail address: eabraham{at}uab.edu
4 Abbreviations used in this paper: PS, phosphatidylserine; HMGB-1, high mobility group protein-1 protein; PI, propidium iodide; BAL, bronchoalveolar lavage; PC, phosphatidylcholine; FRET, fluorescence resonance energy transfer; NBD, 7-nitro-2,1,3-benzoxadiazol-4-yl.
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