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

Fan, Zhichao; McArdle, Sara; Marki, Alex; Mikulski, Zbigniew; Gutierrez, Edgar; Engelhardt, Britta; Deutsch, Urban; Ginsberg, Mark; Groisman, Alex; Ley, Klaus (2016). Neutrophil recruitment limited by high-affinity bent β2 integrin binding ligand in cis. Nature communications, 7, p. 12658. Nature Publishing Group 10.1038/ncomms12658

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Engelhardt, Britta and Deutsch, Urban

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

22 May 2017 11:22

Last Modified:

28 May 2017 02:16

Publisher DOI:

10.1038/ncomms12658

PubMed ID:

27578049

BORIS DOI:

10.7892/boris.95349

URI:

https://boris.unibe.ch/id/eprint/95349

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