title: Cleavage of annexin A1 by ADAM10 during secondary necrosis generates a monocytic "find-me" signal.
abstract: Annexin A1 is an intracellular calcium/phospholipid-binding protein that is involved in membrane organization and the regulation of the immune system. It has been attributed an anti-inflammatory role at various control levels, and recently we could show that annexin A1 externalization during secondary necrosis provides an important fail-safe mechanism counteracting inflammatory responses when the timely clearance of apoptotic cells has failed. As such, annexin A1 promotes the engulfment of dying cells and dampens the postphagocytic production of proinflammatory cytokines. In our current follow-up study, we report that exposure of annexin A1 during secondary necrosis coincided with proteolytic processing within its unique N-terminal domain by ADAM10. Most importantly, we demonstrate that the released peptide and culture supernatants of secondary necrotic, annexin A1-externalizing cells induced chemoattraction of monocytes, which was clearly reduced in annexin A1- or ADAM10-knockdown cells. Thus, altogether our findings indicate that annexin A1 externalization and its proteolytic processing into a chemotactic peptide represent final events during apoptosis, which after the transition to secondary necrosis contribute to the recruitment of monocytes and the prevention of inflammation.
authors: Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany.
authors: Karin E
authors: KE
authors: Blume
authors: Szabolcs
authors: S
authors: Soeroes
authors: Hildegard
authors: H
authors: Keppeler
authors: Stefan
authors: S
authors: Stevanovic
authors: Dorothee
authors: D
authors: Kretschmer
authors: Maren
authors: M
authors: Rautenberg
authors: Sebastian
authors: S
authors: Wesselborg
authors: Kirsten
authors: K
authors: Lauber
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017305:Annexin A1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002630:Chemotactic Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology*; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020298:U937 Cells
chemical_list: D017305:Annexin A1; D002630:Chemotactic Factors; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human