The influence on the immunomodulatory effects of dying and dead cells of Annexin V.
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.
Munoz
Luis E
LE
Institute for Clinical Immunology, Department of Internal Medicne 3, Friedrich-Alexander-University of Erlangen-Nuremberg, Glueckstrasse 4a, 91054 Erlangen, Germany.
Franz
Sandra
S
Pausch
Friederike
F
Fürnrohr
Barbara
B
Sheriff
Ahmed
A
Vogt
Birgit
B
Kern
Peter M
PM
Baum
Wolfgang
W
Stach
Christian
C
von Laer
Dorothee
D
Brachvogel
Bent
B
Poschl
Ernst
E
Herrmann
Martin
M
Gaipl
Udo S
US
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
D017304:Annexin A5; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007155:Immunologic Factors; D010718:Phosphatidylserines