Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart

Neutrophils migrate to infected mucosal sites that they protect against inv ading pathogens. Their interaction with the epithelial barrier is controlle d by CXC chemokines and by their receptors. This study examined the change in susceptibility to urinary tract infection (UTI) after deletion of the mu rine interleukin 8 receptor homologue (mIL-8Rh). Experimental UTIs in contr ol mice stimulated an epithelial chemokine response and increased chemokine receptor expression. Neutrophils migrated through the tissues to the epith elial barrier that they crossed into the lumen, and the mice developed pyur ia. In mIL-8Rh knockout (KO) mice, the chemokine response was intact, but t he epithelial cells failed to express IL-8R, and neutrophils accumulated in the tissues. The KO mice were unable to clear bacteria from kidneys and bl adders and developed bacteremia and symptoms of systemic disease, but contr ol mice were fully resistant to infection. The experimental UTI model demon strated that IL-8R-dependent mechanisms control the urinary tract defense, and that neutrophils are essential host effector cells. Patients prone to a cute pyelonephritis also showed low CXC chemokine receptor 1 expression com pared with age-matched controls, suggesting that chemokine receptor express ion may also influence the susceptibility to UTIs in humans. The results pr ovide a first molecular clue to disease susceptibility of patients prone to acute pyelonephritis.