title: Cell surface externalization of annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis.
abstract: The engulfment of apoptotic cells is of crucial importance for tissue homeostasis in multicellular organisms. A failure of this process results in secondary necrosis triggering proinflammatory cytokine production and autoimmune disease. In the present study, we investigated the role of annexin A1, an intracellular protein that has been implicated in the efficient removal of apoptotic cells. Consistent with its function as bridging protein in the phagocyte synapse, opsonization of apoptotic cells with purified annexin A1 strongly enhanced their phagocytic uptake. A detailed analysis, however, surprisingly revealed that annexin A1 was hardly exposed to the cell surface of primary apoptotic cells, but was strongly externalized only on secondary necrotic cells. Interestingly, while the exposure of annexin A1 failed to promote the uptake of these late secondary necrotic cells, it efficiently prevented induction of cytokine production in macrophages during engulfment of secondary necrotic cells. Our results therefore suggest that annexin A1 exposure during secondary necrosis provides an important failsafe mechanism counteracting inflammatory responses, even when the timely clearance of apoptotic cells has failed.
authors.affiliation: Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Blume
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Soeroes
authors.forename: Michaela
authors.initials: M
authors.lastname: Waibel
authors.forename: Hildegard
authors.initials: H
authors.lastname: Keppeler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lauber
mesh_terms: D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology*; D019169:Jurkat Cells; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D009336:Necrosis / Q000276:immunology / Q000517:prevention & control; D010587:Phagocytosis / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008565:Membrane Proteins