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

Abstract

Neutrophils migrate to infected mucosal sites that they protect against invading pathogens. Their interaction with the epithelial barrier is controlled by CXC chemokines and by their receptors. This study examined the change in susceptibility to urinary tract infection (UTI) after deletion of the murine interleukin 8 receptor homologue (mIL-8Rh). Experimental UTIs in control mice stimulated an epithelial chemokine response and increased chemokine receptor expression. Neutrophils migrated through the tissues to the epithelial barrier that they crossed into the lumen, and the mice developed pyuria. In mIL-8Rh knockout (KO) mice, the chemokine response was intact, but the epithelial cells failed to express IL-8R, and neutrophils accumulated in the tissues. The KO mice were unable to clear bacteria from kidneys and bladders and developed bacteremia and symptoms of systemic disease, but control mice were fully resistant to infection. The experimental UTI model demonstrated that IL-8R–dependent mechanisms control the urinary tract defense, and that neutrophils are essential host effector cells. Patients prone to acute pyelonephritis also showed low CXC chemokine receptor 1 expression compared with age-matched controls, suggesting that chemokine receptor expression may also influence the susceptibility to UTIs in humans. The results provide a first molecular clue to disease susceptibility of patients prone to acute pyelonephritis.

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

“…Disease severity is controlled by the murine IL-8R homologue (mIL-8Rh) and mIL-8Rh -/-mice develop acute pyelonephritis, bacteremia and renal scarring due to neutrophil entrapment in the tissues [15,40]. Genetic defects in the IL-8R have also been detected in patients prone to acute pyelonephritis [41]. The present study emphasized the potential for host control of unresponsiveness to UTI, as abrogated TLR4 signalling protected against inflammation and symptoms.…”

Neutrophil recruitment in immunized mice depends on MIP‐2 inducing the sequential release of MIP‐1α, TNF‐α and LTB4

“…In this context, it was observed that the use of peptide and non-peptide CXCR2 antagonists, truncated GROa(8-73) and SB 455821, respectively, blocked the in vitro and in vivo MIP-2-induced neutrophil migration [10,29]. In addition, it was demonstrated that the genetic disruption of CXCR2 blocked the neutrophil recruitment observed in inflammatory disease models of polynephritis and Lyme arthritis, resulting in resistance to pathology [30][31][32]. Repertaxin is a novel noncompetitive allosteric inhibitor of CXCR1 and CXCR2, and is an active blocker of neutrophil chemotaxis in humans and rodents [33][34][35].…”

Renal Collecting Duct Epithelial Cells React to Pyelonephritis-Associated Escherichia coli by Activating Distinct TLR4-Dependent and -Independent Inflammatory Pathways

“…However, the two UPEC strains induced markedly different stimulation profiles of proinflammatory mediators in the kidneys of Lps n and Lps d mice, suggesting that different bacterial factors produced by the UPECs may be implicated in the activation of distinct TLR4-dependent and -independent signaling pathways. MIP-2 and its human counterpart IL-8 play key roles in the migration of neutrophils to infected mucosal sites to protect them against invading pathogens (41,42,57). The two UPECs stimulated MIP-2 mRNA expression and protein secretion in both Lps n kidney and cultured Lps n MCDs through a main TLR4-dependent pathway.…”