Dr. Böttcher, Dr. Gaipl, and Ms Fürnrohr contributed equally to this work.
Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages
Article first published online: 28 FEB 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 3, pages 927–938, March 2006
How to Cite
Böttcher, A., Gaipl, U. S., Fürnrohr, B. G., Herrmann, M., Girkontaite, I., Kalden, J. R. and Voll, R. E. (2006), Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages. Arthritis & Rheumatism, 54: 927–938. doi: 10.1002/art.21660
- Issue published online: 28 FEB 2006
- Article first published online: 28 FEB 2006
- Manuscript Accepted: 1 DEC 2005
- Manuscript Received: 24 JAN 2005
- Interdisciplinary Center for Clinical Research. Grant Numbers: N2, B28, A4
- University Hospital of the University of Erlangen-Nürnberg and the European Commissions. Grant Number: QLK3-CT-2002-02017_APOCLEAR
- German Research Society. Grant Numbers: B3, B5
- Lupus Erythemathodes Selbsthilfegemeinschaft eV.
- German Research Societym. Grant Number: GRK 592 from the DFG
Uningested dead cells may be an important source of autoantigens and may trigger autoimmune diseases such as systemic lupus erythematosus (SLE). Multiple receptors involved in the clearance of apoptotic cells have been described; however, little is known about the receptors and ligands involved in uptake of necrotic cells that release autoantigens as well.
The uptake of autologous necrotic peripheral blood lymphocytes into human monocyte-derived macrophages was qualitatively and quantitatively monitored by confocal microscopy and 2-color flow cytometry, respectively. Blocking experiments were performed to examine the receptors and molecules involved in the phagocytosis of necrotic cells. Cytokine secretion by lipopolysaccharide-activated monocytes and macrophages was determined by enzyme-linked immunosorbent assay.
Phosphatidylserine, which was exposed on necrotic as well as apoptotic cells, promoted the recognition and removal of primary necrotic lymphocytes. Several macrophage receptor systems, including the thrombospondin–CD36–αvβ3 complex, CD14, and the complement component C1q, contributed to the engulfment of necrotic cells. Necrotic peripheral blood lymphocytes slightly increased the lipopolysaccharide-induced secretion of interleukin-10 and reduced the secretion of tumor necrosis factor α in monocytes and macrophages.
Our results indicate that at least some of the receptors and adaptors mediating the uptake of apoptotic cells are also involved in the clearance of necrotic cells. Hence, necrotic cells engage phagocyte receptors such as CD36, which mediate antiinflammatory signals from apoptotic cells. Necrotic cells consequently also have the potency to provide antiinflammatory signals to phagocytes; however, these signals may be overridden by proinflammatory factors released during necrosis. These findings have implications regarding the etiopathogenesis of autoimmune diseases such as SLE, in which impaired clearance of dead cells may foster autoimmunity by the release of potential autoantigens.