Abstract
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.
Highlights
Neutrophil chemotaxis is a complex process involving close coordination of signaling pathways, the actin cytoskeleton, and effector adhesion molecules such as integrins
A much larger quantity of clustered LFA-1 was found on cells migrating to interleukin 8 (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
Summary
Neutrophil chemotaxis is a complex process involving close coordination of signaling pathways, the actin cytoskeleton, and effector adhesion molecules such as integrins. Two integrins have been shown to be central to neutrophil chemotaxis: LFA1 (CD11a/CD18) and Mac-1 (CD11b/CD18) (Lindbom and Werr, 2002). The importance of these integrins for neutrophil chemotaxis was first identified in leukocyte adhesion deficiency type I (LAD I) patients. These patients have a genetic defect in CD18, the common subunit for both LFA-1 and Mac-1. Little is known about the regulation of LFA-1, Mac-1 and ␣4-integrin during chemotaxis, or if these integrins are regulated differentially by different chemoattractants How these molecules respond in the presence of competing chemoattractant gradients remains to be elucidated
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