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Published online before print September 27, 2006
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0306166

Received for publication March 5, 2006.
Revised July 31, 2006.
Accepted for publication August 6, 2006.

Article

The influence on the immunomodulatory effects of dying and dead cells of Annexin V

Luis E. Munoz *, Sandra Franz *, Friederike Pausch {dagger}, Barbara Fürnrohr {ddagger}, Ahmed Sheriff *, Birgit Vogt *, Peter M. Kern {sect}, Wolfgang Baum *, Christian Stach *, Dorothee von Laer , Bent Brachvogel {dagger}, Ernst Poschl {dagger}, Martin Herrmann *, and Udo S. Gaipl *{dagger}@

*Institute for Clinical Immunology, Department of Internal Medicine 3, {dagger}Department of Experimental Medicine I and {ddagger}IZKF Research Group 2, Nikolaus Fiebiger Centre of Molecular Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany; {sect}Franz von Prümmer Klinik, Akutklinik für Rheumatologie und Allgemeinkrankenhaus Bahnhofstrasse 16, Germany; and Chemotherapeutisches Forschungsinstitut Georg Speyer Haus, Frankfurt, Germany

@ To whom correspondence should be addressed. E-mail: udo.gaipl{at}med3.imed.uni-erlangen.de.


  Abstract

Apoptotic and necrotic cells expose phosphatidylserine (PS). This membrane modification ensures a swift recognition and uptake by phagocytes of the dying and dead cells. Annexin V (AxV) preferentially binds to anionic phospholipids and thereby, modulates the clearance process. First, we analyzed the influence of AxV on the immunogenicity of apoptotic cells. The addition to apoptotic cells of AxV prior to their injection into mice increased their immunogenicity significantly. Next, we studied the influence of endogenous AxV on the allogeneic reaction against apoptotic and necrotic cells. To preserve heat-labile, short-lived "danger signals," we induced necrosis by mechanical stress. Wild-type mice showed a strong, allogeneic delayed-type hypersensitivity (DTH) reaction. In contrast, AxV-deficient animals showed almost no allogeneic DTH reaction, indicating that endogenous AxV increases the immune response against dead cells. Furthermore, AxV-deficient macrophages had a higher immunosuppressive potential in vitro. Next, we analyzed the influence of AxV on chronic macrophage infection with HIV-1, known to expose PS on its surface. The infectivity in human macrophages of HIV-1 was reduced significantly in the presence of AxV. Finally, we show that AxV also blocked the in vitro uptake by macrophages of primary necrotic cells. Similar to apoptotic cells, necrotic cells generated by heat treatment displayed an anti-inflammatory activity. In contrast, mechanical stress-induced necrotic cells led to a decreased secretion of IL-10, indicating a more inflammatory potent- ial. From the experiments presented above, we conclude that AxV influences the clearance of several PS-exposing particles such as viruses, dying, and dead cells.

Key Words: immunogenicity • apoptotic cells • necrotic cells • clearance • macrophages




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