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A negative feedback loop regulates integrin inactivation and promotes neutrophil recruitment to inflammatory sites

Research output: Contribution to journalArticle

  • Barry McCormick
  • Helen E. Craig
  • Julia Y. Chu
  • Leo M. Carlin
  • Marta Canel
  • Florian Wollweber
  • Matilda Toivakka
  • Melina Michael
  • Anne L. Astier
  • Laura Norton
  • Johanna Lilja
  • Jennifer M. Felton
  • Takehiko Sasaki
  • Johanna Ivaska
  • Ingeborg Hers
  • Ian Dransfield
  • Adriano G. Rossi
  • Sonja Vermeren
Original languageEnglish
Number of pages11
JournalJournal of Immunology
Volume203
Issue number9
DOIs
DateAccepted/In press - 16 Jul 2019
DatePublished (current) - 19 Aug 2019

Abstract

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.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via American Association of Immunologists at https://www.jimmunol.org/content/early/2019/08/16/jimmunol.1900443/tab-article-info . Please refer to any applicable terms of use of the publisher.

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