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McCormick, Barry; Craig, Helen E.; Chu, Julia Y.; Carlin, Leo M.; Canel, Marta; Wollweber, Florian; Toivakka, Matilda; Michael, Melina; Astier, Anne L.; Norton, Laura; Lilja, Johanna; Felton, Jennifer M.; Sasaki, Takehiko; Ivaska, Johanna; Hers, Ingeborg; Dransfield, Ian; Rossi, Adriano G.; Vermeren, Sonja

A Negative Feedback Loop Regulates Integrin Inactivation and Promotes Neutrophil Recruitment to Inflammatory Sites

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  • Medientyp: E-Artikel
  • Titel: A Negative Feedback Loop Regulates Integrin Inactivation and Promotes Neutrophil Recruitment to Inflammatory Sites
  • Beteiligte: McCormick, Barry; Craig, Helen E.; Chu, Julia Y.; Carlin, Leo M.; Canel, Marta; Wollweber, Florian; Toivakka, Matilda; Michael, Melina; Astier, Anne L.; Norton, Laura; Lilja, Johanna; Felton, Jennifer M.; Sasaki, Takehiko; Ivaska, Johanna; Hers, Ingeborg; Dransfield, Ian; Rossi, Adriano G.; Vermeren, Sonja
  • Erschienen: The American Association of Immunologists, 2019
  • Erschienen in: The Journal of Immunology
  • Sprache: Englisch
  • DOI: 10.4049/jimmunol.1900443
  • ISSN: 0022-1767; 1550-6606
  • Schlagwörter: Immunology ; Immunology and Allergy
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Neutrophils are abundant circulating leukocytes that are rapidly recruited to sites of inflammation in an integrin-dependent fashion. Contrasting with the well-characterized regulation of integrin activation, mechanisms regulating integrin inactivation remain largely obscure. Using mouse neutrophils, we demonstrate in this study that the GTPase activating protein ARAP3 is a critical regulator of integrin inactivation; experiments with Chinese hamster ovary cells indicate that this is not restricted to neutrophils. Specifically, ARAP3 acts in a negative feedback loop downstream of PI3K to regulate integrin inactivation. Integrin ligand binding drives the activation of PI3K and of its effectors, including ARAP3, by outside-in signaling. ARAP3, in turn, promotes localized integrin inactivation by negative inside-out signaling. This negative feedback loop reduces integrin-mediated PI3K activity, with ARAP3 effectively switching off its own activator, while promoting turnover of substrate adhesions. In vitro, ARAP3-deficient neutrophils display defective PIP3 polarization, adhesion turnover, and transendothelial migration. In vivo, ARAP3-deficient neutrophils are characterized by a neutrophil-autonomous recruitment defect to sites of inflammation.</jats:p>
  • Zugangsstatus: Freier Zugang