Transepithelial neutrophil migration is CXCR1 dependent in vitro and is defective in IL-8 receptor knockout mice

Neutrophil migration across infected mucosal surfaces is chemokine dependen t, but the role of chemokine receptors has not been investigated. In this s tudy, chemokine receptors were shown to be expressed by epithelial cells li ning the urinary tract, and to play an essential role for neutrophil migrat ion across the mucosal barrier. Uroepithelial CXCR1 and CXCR2 expression wa s detected in human urinary tract biopsies, and in vitro infection of human uroepithelial cell lines caused a dramatic increase in both receptors. As a consequence, there was higher binding of IL-8 to the cells and the IL-8-d ependent neutrophil migration across the infected epithelial cell layers wa s enhanced. Abs to IL-8 or to the CXCR1 receptor inhibited this increase by 60% (p < 0.004), but anti-CXCR2 Abs had no effect, suggesting that CXCR1 w as the more essential receptor in this process. Similar observations were m ade in the mouse urinary tract, where experimental infection stimulated epi thelial expression of the murine IL-8 receptor, followed by a rapid flux of neutrophils into the lumen. IL-8 receptor knockout mice, in contrast, fail ed to express the receptor, their neutrophils were unable to cross the epit helial barrier, and accumulated in massive numbers in the tissues. These re sults demonstrate that epithelial cells express CXC receptors and that infe ction increases receptor expression. Furthermore, we show that CXCR1 is req uired for neutrophil migration across infected epithelial cell layers in vi tro, and that the murine IL-8 receptor is needed for neutrophils to cross t he infected mucosa of the urinary tract in vivo.