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Neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis

Neutrophils are essential for innate immunity and inflammation and many neutrophil functions are β(2) 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 th...

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Autores principales: Fan, Zhichao, McArdle, Sara, Marki, Alex, Mikulski, Zbigniew, Gutierrez, Edgar, Engelhardt, Britta, Deutsch, Urban, Ginsberg, Mark, Groisman, Alex, Ley, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013657/
https://www.ncbi.nlm.nih.gov/pubmed/27578049
http://dx.doi.org/10.1038/ncomms12658
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author Fan, Zhichao
McArdle, Sara
Marki, Alex
Mikulski, Zbigniew
Gutierrez, Edgar
Engelhardt, Britta
Deutsch, Urban
Ginsberg, Mark
Groisman, Alex
Ley, Klaus
author_facet Fan, Zhichao
McArdle, Sara
Marki, Alex
Mikulski, Zbigniew
Gutierrez, Edgar
Engelhardt, Britta
Deutsch, Urban
Ginsberg, Mark
Groisman, Alex
Ley, Klaus
author_sort Fan, Zhichao
collection PubMed
description Neutrophils are essential for innate immunity and inflammation and many neutrophil functions are β(2) 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 β(2) integrins on human neutrophils acquire an unexpected E(−)H(+) conformation. E(−)H(+) β(2) 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.
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spelling pubmed-50136572016-09-20 Neutrophil recruitment limited by high-affinity bent β(2) 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 Nat Commun Article Neutrophils are essential for innate immunity and inflammation and many neutrophil functions are β(2) 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 β(2) integrins on human neutrophils acquire an unexpected E(−)H(+) conformation. E(−)H(+) β(2) 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. Nature Publishing Group 2016-08-31 /pmc/articles/PMC5013657/ /pubmed/27578049 http://dx.doi.org/10.1038/ncomms12658 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Fan, Zhichao
McArdle, Sara
Marki, Alex
Mikulski, Zbigniew
Gutierrez, Edgar
Engelhardt, Britta
Deutsch, Urban
Ginsberg, Mark
Groisman, Alex
Ley, Klaus
Neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis
title Neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis
title_full Neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis
title_fullStr Neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis
title_full_unstemmed Neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis
title_short Neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis
title_sort neutrophil recruitment limited by high-affinity bent β(2) integrin binding ligand in cis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013657/
https://www.ncbi.nlm.nih.gov/pubmed/27578049
http://dx.doi.org/10.1038/ncomms12658
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