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Elastase Release by Transmigrating Neutrophils Deactivates Endothelial-bound SDF-1 and Attenuates Subsequent T Lymphocyte Transendothelial Migration

¹ Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
² Unite Chimie Organique, Institut Pasteur, Paris Cedex, France 75724
³ Unite de D'Immunologie Virale, Institut Pasteur, Paris Cedex, France 75724
⁴ Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel 76100

Address correspondence to Francis W. Luscinskas, Dept. of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital, 77 Ave. Louis Pasteur NRB 752P, Boston, MA 02115. Phone: (617) 732-6004; Fax: (617) 732-5933; e-mail: fluscinskas{at}rics.bwh.harvard.edu

Leukocyte trafficking to sites of inflammation follows a defined temporal pattern, and evidence suggests that initial neutrophil transendothelial migration modifies endothelial cell phenotype. We tested the hypothesis that preconditioning of human umbilical vein endothelial cells (HUVEC) by neutrophils would also modify the subsequent transendothelial migration of T lymphocytes across cytokine-stimulated HUVEC in an in vitro flow assay. Using fluorescence microscopy, preconditioning of HUVEC by neutrophils was observed to significantly reduce the extent of subsequent stromal cell–derived factor-1 (SDF-1 [CXCL12])-mediated T lymphocyte transendothelial migration, without reducing accumulation. In contrast, recruitment of a second wave of neutrophils was unaltered. Conditioned medium harvested after transendothelial migration of neutrophils or supernatants from stimulated neutrophils mediated a similar blocking effect, which was negated using a specific neutrophil elastase inhibitor. Furthermore, T lymphocyte transendothelial migration was inhibited by treatment of HUVEC with purified neutrophil elastase, which selectively cleaved the amino terminus of HUVEC-bound SDF-1, which is required for its chemotactic activity. The reduction in T lymphocyte transendothelial migration was not observed using a different chemokine, ELC (CCL19), and was not reversed by replenishment of SDF-1, indicating endothelial retention of the inactivated chemokine. In summary, transmigrating neutrophils secrete localized elastase that is protected from plasma inhibitors, and thereby modulate trafficking of other leukocyte subsets by altering the endothelial-associated chemotactic activities.

Key Words: endothelium • chemokine • inflammation • lymphocyte • imaging • diapedesis

Abbreviations used in this paper: DIC, differential interference contrast; EC, endothelial cell; EI, elastase inhibitor; HNE, human neutrophil elastase; HRP, horseradish peroxidase; HUVEC, human umbilical vein ECs; SDF-1, stromal cell derived factor-1.

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