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

McCormick, B. et al. (2019) A negative feedback loop regulates integrin inactivation and promotes neutrophil recruitment to inflammatory sites. Journal of Immunology, 203(6), pp. 1579-1588. (doi: 10.4049/jimmunol.1900443) (PMID:31427445) (PMCID:PMC6731454)

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. [Abstract copyright: Copyright © 2019 The Authors.]

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carlin, Dr Leo
• Authors: McCormick, B., Craig, H. E., Chu, J. Y., Carlin, L. M., Canel, M., Wollweber, F., Toivakka, M., Michael, M., Astier, A. L., Norton, L., Lilja, J., Felton, J. M., Sasaki, T., Ivaska, J., Hers, I., Dransfield, I., Rossi, A. G., and Vermeren, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Immunology
• Publisher: American Association of Immunologists
• ISSN: 0022-1767
• ISSN (Online): 1550-6606
• Published Online: 09 September 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Journal of Immunology 203(6): 1579-1588
• Publisher Policy: Reproduced under a Creative Commons License