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Nat Commun. 2016 Aug 31;7:12658. doi: 10.1038/ncomms12658.

Neutrophil recruitment limited by high-affinity bent β2 integrin binding ligand in cis.

Author information

1
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, California 92037, USA.
2
Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
3
Department of Physics, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
4
Theodor Kocher Institute, University of Bern, 1 Freiestrasse, 3012 Bern, Switzerland.
5
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.

Abstract

Neutrophils are essential for innate immunity and inflammation and many neutrophil functions are β2 integrin-dependent. Integrins can extend (E(+)) and acquire a high-affinity conformation with an 'open' headpiece (H(+)). The canonical switchblade model of integrin activation proposes that the E(+) conformation precedes H(+), and the two are believed to be structurally linked. Here we show, using high-resolution quantitative dynamic footprinting (qDF) microscopy combined with a homogenous conformation-reporter binding assay in a microfluidic device, that a substantial fraction of β2 integrins on human neutrophils acquire an unexpected E(-)H(+) conformation. E(-)H(+) β2 integrins bind intercellular adhesion molecules (ICAMs) in cis, which inhibits leukocyte adhesion in vitro and in vivo. This endogenous anti-inflammatory mechanism inhibits neutrophil aggregation, accumulation and inflammation.

PMID:
27578049
PMCID:
PMC5013657
DOI:
10.1038/ncomms12658
[Indexed for MEDLINE]
Free PMC Article

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