title: Integrins are Mechanosensors That Modulate Human Eosinophil Activation.
abstract: Eosinophil migration to the lung is primarily regulated by the eosinophil-selective family of eotaxin chemokines, which mobilize intracellular calcium (Ca(2+)) and orchestrate myriad changes in cell structure and function. Eosinophil function is also known to be flow-dependent, although the molecular cognate of this mechanical response has yet to be adequately characterized. Using confocal fluorescence microscopy, we determined the effects of fluid shear stress on intracellular calcium concentration ([Ca(2+)]i) in human peripheral blood eosinophils by perfusing cells in a parallel-plate flow chamber. Our results indicate that fluid perfusion evokes a calcium response that leads to cell flattening, increase in cell area, shape change, and non-directional migration. None of these changes are seen in the absence of a flow stimulus, and all are blocked by chelation of intracellular Ca(2+) using BAPTA. These changes are enhanced by stimulating the cells with eotaxin-1. The perfusion-induced calcium response (PICR) could be blocked by pre-treating cells with selective (CDP-323) and non-selective (RGD tripeptides) integrin receptor antagonists, suggesting that α4β7/α4β1 integrins mediate this response. Overall, our study provides the first pharmacological description of a molecular mechanosensor that may collaborate with the eotaxin-1 signaling program in order to control human eosinophil activation.
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital , Hamilton, ON , Canada ; Department of Biomedical Sciences, McMaster University , Hamilton, ON , Canada.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ahmadzai
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital , Hamilton, ON , Canada ; Department of Medicine, McMaster University , Hamilton, ON , Canada.
authors.forename: Mike
authors.initials: M
authors.lastname: Small
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital , Hamilton, ON , Canada ; Department of Medicine, McMaster University , Hamilton, ON , Canada.
authors.forename: Roma
authors.initials: R
authors.lastname: Sehmi
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital , Hamilton, ON , Canada ; Department of Medicine, McMaster University , Hamilton, ON , Canada.
authors.forename: Gail
authors.initials: G
authors.lastname: Gauvreau
authors.affiliation: Firestone Institute for Respiratory Health, St. Joseph's Hospital , Hamilton, ON , Canada ; Department of Medicine, McMaster University , Hamilton, ON , Canada.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Janssen
keywords: calcium; cytoskeleton; eosinophils; eotaxin; migration