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 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.