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Mobilizing lipocortin 1 in adherent human leukocytes downregulates their transmigration

Abstract

Polymorphonuclear leukocyte (PMN) migration into sites of inflammation is fundamental to the host defense response. Activation of endothelial cells and PMNs increases the expression or activation of adhesion molecules, culminating in rolling and subsequent adherence of these cells to the vascular wall1,2. Further activation of adherent PMNs, possibly by endothelial cell ligands, leads, within a few minutes, to extravasation itself. This process is not clearly understood, but adhesion molecules3 or related proteins4, as well as endogenous chemokines5, may play an important role. The anti–inflammatory glucocorticoids delay extravasation6, which implies that an inhibitory regulatory system exists. Resting PMNs contain abundant cytoplasmic lipocortin 1 (LC1, also called annexin I)7, and the activity profile of this protein8–10 suggests that it could reduce PMN responsiveness. To investigate this we have assessed neutrophil transmigration both in vivo and in vitro and examined the content and subcellular distribution of LCI in PMNs by fluorescence–activated cell–sorting (FACS) analysis, western blotting and confocal microscopy. We report that LCI is mobilized and externalized following PMN adhesion to endothelial monolayers in vitro or to venular endothelium in vivo and that the end point of this process is a negative regulation of PMN transendothelial passage.

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Perretti, M., Croxtall, J., Wheller, S. et al. Mobilizing lipocortin 1 in adherent human leukocytes downregulates their transmigration. Nat Med 2, 1259–1262 (1996). https://doi.org/10.1038/nm1196-1259

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