Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection

Neutrophil migration to infected mucosal sites involves a series of complex interactions with molecules in the lamina propria and at the epithelial ba rrier, Much attention has focussed on the vascular compartment and endothel ial cells, but less is known about the molecular determinants of neutrophil behavior in the periphery. We have studied urinary tract infections (UTIs) to determine the events that initiate neutrophil recruitment and interacti ons of the recruited neutrophils with the mucosal barrier, Bacteria activat e a chemokine response in uroepithelial cells, and the chemokine repertoire depends on the bacterial virulence factors and on the specific signaling p athways that they activate. In addition, epithelial chemokine receptor expr ession is enhanced. Interleukin (IL)-8 and CXCR1 direct neutrophil migratio n across the epithelial barrier into the lumen. Indeed, mIL-8Rh knockout mi ce showed impaired transepithelial neutrophil migration, with tissue accumu lation of neutrophils, and these mice developed renal scarring. They had a defective antibacterial defense and developed acute pyelonephritis with bac teremia. Low CXCR1 expression was also detected in children with acute pyel onephritis. These results demonstrate that chemokines and chemokine recepto rs are essential to orchestrate a functional antimicrobial defense of the u rinary tract mucosa, Mutational inactivation of the IL-8R caused both acute disease and chronic tissue damage.