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

  • Author(s): Fan, Zhichao
  • McArdle, Sara
  • Marki, Alex
  • Mikulski, Zbigniew
  • Gutierrez, Edgar
  • Engelhardt, Britta
  • Deutsch, Urban
  • Ginsberg, Mark
  • Groisman, Alex
  • Ley, Klaus
  • et al.
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.

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