2016 Nature Communications.pdf
2019-03-04T18:54:44Z (GMT) by
Neutrophils are essential for innate immunity and inflammation and many neutrophil<br>functions are b2 integrin-dependent. Integrins can extend (Eþ) and acquire a high-affinity<br>conformation with an ‘open’ headpiece (Hþ). The canonical switchblade model of integrin<br>activation proposes that the Eþ conformation precedes Hþ, and the two are believed to be<br>structurally linked. Here we show, using high-resolution quantitative dynamic footprinting<br>(qDF) microscopy combined with a homogenous conformation-reporter binding assay in a<br>microfluidic device, that a substantial fraction of b2 integrins on human neutrophils acquire an<br>unexpected EHþ conformation. EHþ b2 integrins bind intercellular adhesion molecules<br>(ICAMs) in cis, which inhibits leukocyte adhesion in vitro and in vivo. This endogenous antiinflammatory<br>mechanism inhibits neutrophil aggregation, accumulation and inflammation.