2016 Nature Communications.pdf

Neutrophils are essential for innate immunity and inflammation and many neutrophil functions are b2 integrin-dependent. Integrins can extend (Eþ) and acquire a high-affinity conformation with an ‘open’ headpiece (Hþ). The canonical switchblade model of integrin activation proposes that the Eþ conformation precedes Hþ, 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 b2 integrins on human neutrophils acquire an unexpected EHþ conformation. EHþ b2 integrins bind intercellular adhesion molecules (ICAMs) in cis, which inhibits leukocyte adhesion in vitro and in vivo. This endogenous antiinflammatory mechanism inhibits neutrophil aggregation, accumulation and inflammation.