CC chemokines induce P‐selectin‐dependent neutrophil rolling and recruitment in vivo : intermediary role of mast cells

Based on in vitro chemotaxis experiments, it is widely held that CC chemokines, such as macrophage inflammatory protein‐1α (MIP‐1α) and macrophage chemotactic protein‐1 (MCP‐1) mainly support lymphocyte trafficking. The objective of the present study was to examine the role of MIP‐1α and MCP‐1 in neutrophil recruitment in vivo by use of intravital microscopy of the mouse cremaster microcirculation. MIP‐1α and MCP‐1 caused a dose‐dependent increase in leukocyte rolling, adhesion and recruitment. Indeed, neutrophils comprised more than 85% of the leukocyte response to MIP‐1α and MCP‐1. An anti‐P‐selectin antibody reduced MIP‐1α and MCP‐1‐provoked leukocyte rolling by more than 94%. Concomitantly, firm adhesion and extravasation of neutrophils in response to MIP‐1α and MCP‐1 challenge were significantly decreased by more than 78 and 84%, respectively. In contrast, an anti‐E‐selectin antibody had no influence on CC chemokine‐induced neutrophil recruitment. Flow cytometric analysis revealed that MIP‐1α and MCP‐1 had no effect on P‐selectin expression on endothelial cells, suggesting that neutrophil recruitment elicited by CC chemokines in vivo is not mediated via a direct effect on the endothelium but rather via an indirect effect involving activation of an intermediary tissue cell. Indeed, it was found that MIP‐1α‐induced neutrophil accumulation was significantly decreased by 58% in mast cell‐deficient mice. These findings demonstrate that CC chemokines trigger P‐selectin‐dependent rolling and tissue recruitment of neutrophils via tissue mast cells in vivo and suggest that CC chemokines may also be important targets in neutrophil‐mediated tissue damage in multicellular organs.British Journal of Pharmacology (2003) 138 , 698–706. doi: 10.1038/sj.bjp.0705094