Shear-induced resistance to neutrophil activation via the formyl peptide receptor

摘要

The ability of activated leukocytes to retract pseudopods in response to fluid shear stress may be a critical mechanism to downregulate inflammation and maintain stable circulation. By measuring earlier indicators of leukocyte activation such as L-selectin shedding and β2 integrin activation, which precede morphological changes, we have found that exposure to physiological levels of fluid shear stress makes neutrophils more resistant to activation via the formyl peptide receptor (FPR), a chemoattractant G-protein coupled receptor (GPCR). After exposure to uniform shear stress in a cone-and-plate viscometer, primary human neutrophils showed a significant reduction to both β2 integrin activation and L-selectin shedding in response to a 0.5 nM concentration of formyl-methionyl-leucyl-phenylalanine (fMLP). Neutrophil resistance to activation was shown via flow cytometry to be shear stress dose-dependent, with neutrophil resistance to increasing from 0.1–4.0 dyn/cm2. Overall, neutrophils acquired a fluid shear stress-induced resistance to activation via FPR. Control of this receptor activity may enhance leukocyte circulation in the bloodstream. This work may also serve as an example for other GPCR mechanosensing phenomena.