title: The influence on the immunomodulatory effects of dying and dead cells of Annexin V.
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 potential. From the experiments presented above, we conclude that AxV influences the clearance of several PS-exposing particles such as viruses, dying, and dead cells.
authors.affiliation: Institute for Clinical Immunology, Department of Internal Medicne 3, Friedrich-Alexander-University of Erlangen-Nuremberg, Glueckstrasse 4a, 91054 Erlangen, Germany.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Munoz
authors.forename: Sandra
authors.initials: S
authors.lastname: Franz
authors.forename: Friederike
authors.initials: F
authors.lastname: Pausch
authors.forename: Barbara
authors.initials: B
authors.lastname: Fürnrohr
authors.forename: Ahmed
authors.initials: A
authors.lastname: Sheriff
authors.forename: Birgit
authors.initials: B
authors.lastname: Vogt
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kern
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.forename: Christian
authors.initials: C
authors.lastname: Stach
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
authors.forename: Ernst
authors.initials: E
authors.lastname: Poschl
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Udo S
authors.initials: US
authors.lastname: Gaipl
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D007111:Immunity, Cellular; D007114:Immunization; D007155:Immunologic Factors / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D009336:Necrosis; D010587:Phagocytosis / Q000276:immunology; D010718:Phosphatidylserines / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007155:Immunologic Factors; D010718:Phosphatidylserines