The emerging roles of neutrophils and macrophages during experimental acute pyelonephritis

Abstract

Abstract Every year, pediatric urinary tract infections (UTI) account for 1.5 million clinician visits in the US alone. Up to 50% of infants with UTI develop a kidney infection (acute pyelonephritis, APN). Despite antibiotic therapy, 15% of children with APN develop renal scarring, which is associated with deterioration in kidney function. Here, we determined the contribution of macrophages and neutrophils to bacterial clearance and the development of kidney fibrosis during experimental APN. Female C3H/HeOuJ mice were treated, via retro-orbital, with one of the following antibodies: isotype IgG (control), anti-Ly6G (depletes neutrophils), anti-CD115 (depletes monocytes), and anti-GR1 (depletes monocytes and neutrophils). After cell depletion, the animals were transurethrally infected with UPEC. Ascending UTI was evaluated via biophotonic imaging. The dynamics of monocytes and neutrophils were determined by flow cytometry. Histopathological scores were performed by H&E and Sirius-Red stainings. Transcriptomic analyses of kidneys were performed using TaqMan Arrays. Our data indicate that neutrophils are required for bacterial clearance, while macrophages promote inflammation in the infected urinary tract. However, the absence of neutrophils results in increased macrophage infiltration and exaggerated macrophage-dependent inflammatory responses in the bladder and kidney. Also, our results demonstrate that macrophage-dependent inflammation during APN, leads to renal scarring and renal functional impairment. These findings uncover a role for the neutrophil-macrophage imbalance in promoting kidney fibrosis during APN. This knowledge will be helpful to develop novel therapies to prevent post-APN scarring in children.