Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration
Migration of activated macrophages is essential for resolution of acute inflammation and the initiation of adaptive immunity. Here, we show that efficient macrophage migration in inflammatory environment depends on Mac‐1 recognition of a binary complex consisting of fibrin within the provisional mat...
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Published in | The EMBO journal Vol. 25; no. 9; pp. 1860 - 1870 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chichester, UK
John Wiley & Sons, Ltd
03.05.2006
Blackwell Publishing Ltd |
Subjects | |
Online Access | Get full text |
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Summary: | Migration of activated macrophages is essential for resolution of acute inflammation and the initiation of adaptive immunity. Here, we show that efficient macrophage migration in inflammatory environment depends on Mac‐1 recognition of a binary complex consisting of fibrin within the provisional matrix and the protease tPA (tissue‐type plasminogen activator). Subsequent neutralization of tPA by its inhibitor PAI‐1 enhances binding of the integrin–protease–inhibitor complex to the endocytic receptor LRP (lipoprotein receptor‐related protein), triggering a switch from cell adhesion to cell detachment. Genetic inactivation of Mac‐1, tPA, PAI‐1 or LRP but not the protease uPA abrogates macrophage migration. The defective macrophage migration in PAI‐1‐deficient mice can be restored by wild‐type but not by a mutant PAI‐1 that does not interact with LRP. In vitro analysis shows that tPA promotes Mac‐1‐mediated adhesion, whereas PAI‐1 and LRP facilitate its transition to cell retraction. Our results emphasize the importance of ordered transitions both temporally and spatially between individual steps of cell migration, and support a model where efficient migration of inflammatory macrophages depends on cooperation of three physiologically prominent systems (integrins, coagulation and fibrinolysis, and endocytosis). |
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Bibliography: | istex:AE0DF0E1E57A05085BB52C2904EFF90E06434985 ark:/67375/WNG-6780C4C5-D Supplementary InformationSupplementary Figure 1Supplementary Figure 2Supplementary Figure 3Supplementary Movie 1Supplementary Movie 2Supplementary Movie 3Supplementary Movie 4Supplementary Movie 5Supplementary Movie 4 ArticleID:EMBJ7601082 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0261-4189 1460-2075 |
DOI: | 10.1038/sj.emboj.7601082 |