Neutrophils are rapidly mobilized from the circulation to sites of inflammation. The mechanisms of neutrophil trafficking in the lung are distinct from those in the periphery, in part because the pulmonary capillaries are the primary site of neutrophil emigration rather than postcapillary venules. Since the diameter of a neutrophil is greater than the width of most pulmonary capillary segments, they must deform to transit through this capillary network, even at homeostasis. Resistance to deformation is primarily due to cortical actin that is rapidly assembled when a neutrophil is exposed to a priming or activation stimulus, resulting in neutrophil stiffening and subsequent sequestration within the pulmonary capillary network. In the current study, we use a microfluidic assay to characterize neutrophil transit through model capillary-like channels. Using techniques from single-particle tracking, we analyzed the cumulative distribution of neutrophil transit times and resolve population-based effects. We found that vinculin, an actin-binding adaptor protein, plays an essential role in neutrophil stiffening in response to formyl-Met-Leu-Phe (fMLP). Vinculin-deficient neutrophils lack the development of a population with slow transit through narrow channels that was observed in both wild-type murine bone marrow neutrophils and HoxB8-conditional progenitor-derived neutrophils. Atomic force microscopy studies provide further evidence that vinculin is required for neutrophil stiffening. Consistent with these findings, we observed that neutrophil sequestration in the lungs of mice is attenuated in the absence of vinculin. Together, our studies indicate that vinculin mediates actin-dependent neutrophil stiffening that leads to their sequestration in capillaries.
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