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Prepublished online as a Blood First Edition Paper on May 29, 2003; DOI 10.1182/blood-2002-10-3312.
Submitted October 31, 2002
Accepted April 25, 2003
The role of macrophages in generation of circulation blood nucleosomes from dead and dying cells
Ning Jiang, Charles F Reich, and David S Pisetsky*
Division of Rhuematology, Duke University Medical Center, Durham, NC, USA; Veterans Administration Hospital, Durham, NC, USA
* Corresponding author; email: piset001{at}mc.duke.edu.
Following apoptosis or necrosis, macrophages clear dead cells by phagocytosis. While this process is efficient, circulating nucleosomes can occur in certain diseases, presumably reflecting either increased production or impaired clearance. To investigate the generation of blood nucleosomes, graded numbers of apoptotic and necrotic cells were administered to normal mice and levels of blood nucleosomes and DNA determined. Using Jurkat cells as a model, nucleosomes and DNA were detected in the blood following administration of 108 apoptotic or necrotic cells per mouse. The kinetics of the response were similar for both types of cell. The role of macrophages was assessed by eliminating these cells with clodronate liposomes or silica. While clodronate treatment alone produced a peak of blood DNA, subsequent administration of dead cells, however, caused no change in DNA levels. In contrast, silica treatment alone did not elicit a blood DNA response, although this treatment limited the rise in DNA from administered cells. Molecular studies showed that the blood DNA following administration of apoptotic or necrotic cells arose from both the mouse as well as the Jurkat cells and had a size distribution consistent with apoptosis. Together, these findings suggest that the generation of blood nucleosomes depends on macrophages, with apoptosis a concomitant of a high burden of dead and dying cells.
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