A Negative Feedback Loop Regulates Integrin Inactivation and Promotes Neutrophil Recruitment to Inflammatory Sites.
Journal
Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R
Informations de publication
Date de publication:
15 09 2019
15 09 2019
Historique:
received:
16
04
2019
accepted:
16
07
2019
pubmed:
21
8
2019
medline:
16
5
2020
entrez:
21
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31427445
pii: jimmunol.1900443
doi: 10.4049/jimmunol.1900443
pmc: PMC6731454
mid: EMS84245
doi:
Substances chimiques
GTPase-Activating Proteins
0
Integrins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1579-1588Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R505651/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/16/21/32083
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A23983
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R014523/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/17/54/32981
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M023060/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/16/27/32213
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M01245X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K501293/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K013386/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors.
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