Contrasting roles for neutrophils and macrophages during experimental pyelonephritis

Abstract Background Urinary tract infections (UTIs) account for 7 million annual office visits and over $1.6 billion in health care spending in the United States. Uropathogenic Escherichia coli (UPEC) initiates over 80% of UTIs. When UPEC ascends from the bladder to the kidneys, the resulting pyelonephritis can lead to renal scarring and end-stage renal disease. Objective We determined the specific roles of monocytes and neutrophils in bacterial clearance and the development of kidney fibrosis during pyelonephritis. Methods Female C3H/HeOuJ mice were treated with neutrophil depleting or monocyte depleting antibodies (monoclonal). After cell depletion, the animals were transurethrally infected with UPEC (CFT073 strain). The progression of UTI was assessed via biophotonic imaging and quantification of bacterial burden in the urinary tract. Transcriptomic analyses were performed using customized TaqMan Arrays. Histopathological scores were performed by H&E and Sirius-Red stainings. The renal function was assessed by measuring blood levels of waste products and electrolytes. Results Monocytes and neutrophils function in a synchronized manner, while neutrophils engulf and eliminate UPEC in the urinary tract, monocytes differentiate into macrophages and promote inflammation in the bladder and kidney to boost the recruitment of neutrophils. However, the absence of neutrophils results in increased macrophage infiltration and exaggerated inflammatory responses in the urinary tract. Macrophage-dependent inflammation leads to renal scarring and renal dysfunction during UTI. Conclusions Our findings uncover a detrimental role for the neutrophil-macrophage imbalance in promoting renal scarring during pyelonephritis. Supported by grants from NIH (K01 DK128379-01)