Interleukin 8 Receptor Deficiency Confers Susceptibility to Acute Experimental Pyelonephritis and May Have a Human Counterpart

doi:10.1084/jem.192.6.881

Published online 18 September 2000.

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© The Rockefeller University Press, 0022-1007/2000/9/881/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 6, September 18, 2000 881-890

Original Article

Interleukin 8 Receptor Deficiency Confers Susceptibility to Acute Experimental Pyelonephritis and May Have a Human Counterpart

Björn Frendéus^a, Gabriela Godaly^a, Long Hang^a, Diana Karpman^a^,b, Ann-Charlotte Lundstedt^a, and Catharina Svanborg^a

^a Department of Microbiology, Immunology, and Glycobiology, Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden
^b Department of Pediatrics, Lund University, S-221 85 Lund, Sweden
Department of Microbiology, Immunology, and Glycobiology, Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62 Lund, Sweden.146-46-137468146-46-173972

Neutrophils migrate to infected mucosal sites that they protectagainst invading pathogens. Their interaction with the epithelialbarrier is controlled by CXC chemokines and by their receptors.This study examined the change in susceptibility to urinarytract infection (UTI) after deletion of the murine interleukin8 receptor homologue (mIL-8Rh). Experimental UTIs in controlmice stimulated an epithelial chemokine response and increasedchemokine receptor expression. Neutrophils migrated throughthe tissues to the epithelial barrier that they crossed intothe lumen, and the mice developed pyuria. In mIL-8Rh knockout(KO) mice, the chemokine response was intact, but the epithelialcells failed to express IL-8R, and neutrophils accumulated inthe tissues. The KO mice were unable to clear bacteria fromkidneys and bladders and developed bacteremia and symptoms ofsystemic disease, but control mice were fully resistant to infection.The experimental UTI model demonstrated that IL-8R–dependentmechanisms control the urinary tract defense, and that neutrophilsare essential host effector cells. Patients prone to acute pyelonephritisalso showed low CXC chemokine receptor 1 expression comparedwith age-matched controls, suggesting that chemokine receptorexpression may also influence the susceptibility to UTIs inhumans. The results provide a first molecular clue to diseasesusceptibility of patients prone to acute pyelonephritis.

Key Words: urinary tract infection • chemokine receptor • mucosal immunity • lipopolysaccharide • knockout mice

Abbreviations used in this paper: CXCR, CXC chemokine receptor;GAPDH, glyceraldehyde 3-phosphate dehydrogenase; KO, knockout;mIL-8Rh, murine IL-8 receptor homologue; MIP, macrophage inflammatoryprotein; UTI, urinary tract infection.

B. Frendéus and G. Godaly contributed equally to thiswork.

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