Natural history of renal scarring in susceptible mIL-8Rh-/- mice

Abstract

Urinary tract infections (UTIs) cause end-stage renal disease (ESRD) but the molecular mechanisms have remained unclear. Recently, the interleukin (IL)-8 receptor was shown to control disease susceptibility in mice and low IL-8 receptor expression was observed in pyelonephritis-prone patients. Intravesical Escherichia coli infection was established in mIL-8Rh-/- or Balb/c control mice. Survival, bacterial persistence, and histology were used as measurements of disease severity. Within 2 days, 19/30 mIL-8Rh-/- mice developed lethal infection with bacteremia. Surviving mice remained infected and developed progressive renal damage with pathologic neutrophil accumulation and abscess formation first under the pelvic epithelium and then throughout the tissue. Recruited immune effector cells were unable to remove the dying neutrophils and frustrated macrophages formed foam cell aggregates. As a result, there was successive destruction of the mucosal barrier, medulla and cortex and necrosis of the renal papilla. The mIL-8Rh+/+ mice all survived and infection was cleared within a few days without symptoms or tissue pathology. mIL-8Rh-/- mice develop acute bacteremic pyelonephritis and renal scarring due to a dysfunctional neutrophil response. The tissue damage resembles human disease, and these mice offer a model system to study the molecular mechanisms of renal scarring.