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First published online 25 October 2005
doi: 10.1242/jcs.02632

Journal of Cell Science 118, 5205-5220 (2005)
Published by The Company of Biologists 2005
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Research Article

Fundamentally different roles for LFA-1, Mac-1 and {alpha}4-integrin in neutrophil chemotaxis

Bryan Heit, Pina Colarusso and Paul Kubes*

Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive, Alberta T2N 4N1, Canada

* Author for correspondence (e-mail: pkubes{at}ucalgary.ca)

Accepted 11 August 2005

Although the LFA-1, Mac-1 and {alpha}4 integrins are required for chemotaxis, it is unknown how they are regulated or what specific role they play. Previously we demonstrated that fMLP and IL-8 induce chemotaxis via the p38 MAPK and phosphoinositide 3-kinase (PI3K) pathways, respectively. Here we show that these chemoattractants also activate and use Mac-1 and LFA-1 in a differential manner during chemotaxis. Using integrin-specific substrata, we demonstrate that cell movement in response to IL-8 is mediated by Mac-1, whereas LFA-1 is required for directional migration. By contrast, chemotaxis to fMLP requires Mac-1 for cell movement, whereas LFA-1 and {alpha}4-integrin are required for directional migration. On serum protein, which contains ligands for LFA-1, Mac-1 and {alpha}4-integrin, chemotaxis to fMLP is dependent on Mac-1, whereas chemotaxis to IL-8 is dependent on LFA-1. These results suggest that Mac-1 is the dominant integrin involved in chemotaxis to fMLP, and LFA-1 is the dominant integrin involved in chemotaxis to IL-8. Consistent with these observations, higher quantities of high-affinity Mac-1 are found on cells chemotaxing to fMLP then on cells chemotaxing to IL-8. Moreover, a much larger quantity of clustered LFA-1 was found on cells migrating to IL-8 compared to cells moving towards fMLP. When cells are presented with competing gradients of fMLP and IL-8, they preferentially migrate towards fMLP and activate/utilize integrins in a manner identical to fMLP alone. Under the same conditions, p38 MAPK inhibition abolishes the preferential migration to fMLP; instead, the cells migrate preferentially towards IL-8. The activation and utilization of integrins under these conditions are consistent with patterns observed with IL-8 alone. Together, these data suggest that fMLP and IL-8 differentially activate integrins for use during chemotaxis, that p38 MAPK is a major mediator in the activation and utilization of integrins, and selective integrin activation occurs during chemotaxis between opposing gradients.

Key words: Chemotaxis, Integrins, Chemokines, Lymphocyte function-associated antigen 1, Mac-1




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