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

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

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)1579-1588
Number of pages10
JournalJournal of Immunology
Volume203
Issue number6
Early online date19 Aug 2019
DOIs
Publication statusPublished - 15 Sep 2019

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