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PMID:18768881

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Citation

Liu, G, Wang, J, Park, YJ, Tsuruta, Y, Lorne, EF, Zhao, X and Abraham, E (2008) High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine. J. Immunol. 181:4240-6

Abstract

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.

Links

PubMed PMC2597447

Keywords

Animals; Apoptosis/immunology; Apoptosis Regulatory Proteins/metabolism; Apoptosis Regulatory Proteins/physiology; Cell Membrane/immunology; Cell Membrane/metabolism; Cells, Cultured; HMGB1 Protein/metabolism; HMGB1 Protein/physiology; Humans; Immune Tolerance; Macrophages, Peritoneal/cytology; Macrophages, Peritoneal/immunology; Macrophages, Peritoneal/metabolism; Mice; Neutrophils/cytology; Neutrophils/immunology; Neutrophils/metabolism; Phagocytosis/immunology; Phosphatidylserines/metabolism; Protein Binding/immunology; Recombinant Proteins/metabolism; Recombinant Proteins/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HMGB1

involved_in

GO:0097350: neutrophil clearance

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:0043277: apoptotic cell clearance

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

enables

GO:0001786: phosphatidylserine binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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